Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade

ABSTRACT

The invention relates to substituted polycyclic aryl and heteroaryl pyrimidinone compounds useful as inhibitors of serine proteases of the coagulation cascade and compounds, compositions and methods for anticoagulant therapy for the treatment and prevention of a variety of thrombotic conditions including coronary artery and cerebrovascular diseases.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority from U.S. Provisional ApplicationSerial No. 60/134,794 filed May 19, 1999, now abandoned, which is herebyincorporated by reference in its entirety.

FIELD OF THE INVENTION

This invention is in the field of anticoagulant therapy, andspecifically relates to compounds, compositions and methods forpreventing and treating thrombotic conditions such as coronary arteryand cerebrovascular disease. More particularly, the invention relates tosubstituted polycyclic aryl and heteroaryl pyrimidinone compounds thatinhibit serine proteases of the coagulation cascade.

BACKGROUND OF THE INVENTION

Physiological systems control the fluidity of blood in mammals [Majerus,P. W. et al: Anticoagulant, Thrombolytic, and Antiplplatelet Drugs. InHardman, J. G. and Limbird, L. E., editors: Goodman & Gilman's ThePharmacological Basis of Therapeutics. 9th edition. New York,McGraw-Hill Book Co., 1996, pp. 1341-1343]. Blood must remain fluidwithin the vascular systems and yet be able to undergo hemostasis,cessation of blood loss from a damaged vessel, quickly. Hemostasis orclotting begins when platelets first adhere to macromolecules insubendothelian regions of an injured and/or damaged vessels. Theseplatelets aggregate to form the primary hemostatic plug and stimulatelocal activation of plasma coagulation factors leading to generation ofa fibrin clot that reinforces the aggregated platelets.

Plasma coagulation factors include factors II, V, VII, VIII, IX, X, XI,and XII; these are also called protease zymogens. These coagulationfactors or protease zymogens are activated by serine proteases leadingto coagulation in a so called “coagulation cascade” or chain reaction[Handin, R. I.: Bleeding and Thrombosis. In Wilson, J., et al. editors:Harrison's Principles of Internal Medicine. 12th Edition, New York,McGraw-Hill Book Co., 1991, p.350]. Coagulation or clotting occurs intwo ways through different pathways. An intrinsic or contact pathwayleads from XII to XIIa to XIa to IXa and to the conversion of X to Xa.Xa with factor Va converts prothrombin (II) to thrombin (IIa) leading toconversion of fibrinogen to fibrin. Polymerization of fibrin leads to afibrin clot. An extrinsic pathway is initiated by the conversion ofcoagulation factor VII to VIIa by Xa. The presence of Tissue Factor andVIIa accelerates formation of Xa in the presence of calcium ion andphospholipids. Formation of Xa leads to thrombin, fibrin, and a fibrinclot as described above. The presence of one or more of these manydifferent coagulation factors and two distinct pathways of clottingcould enable the efficacious, selective control and better understandingof parts of the coagulation or clotting process.

While clotting as a result of an injury to a blood vessel is a criticalphysiological process for mammals such as man, clotting can also lead todisease states. A pathological process called thrombosis results whenplatelet aggregation and/or a fibrin clot blocks (i.e., occludes) ablood vessel. Arterial thrombosis may result in ischemic necrosis of thetissue supplied by the artery. When the thrombosis occurs in a coronaryartery, a myocardial infarction or heart attack can result. A thrombosisoccurring in a vein may cause tissues drained by the vein to becomeedematous and inflamed. Thrombosis of a deep vein may be complicated bya pulmonary embolism. Preventing or treating clots in a blood vessel maybe therapeutically useful by inhibiting formation of blood plateletaggregates, inhibiting formation of fibrin, inhibiting thrombusformation, inhibiting embolus formation, and for treating or preventingunstable angina, refractory angina, myocardial infarction, transientischemic attacks, atrial fibrillation, thrombotic stroke, embolicstroke, deep vein thrombosis, disseminated intravascular coagulation,ocular build up of fibrin, and reocclusion or restenosis of recanalizedvessels.

There have been several reports of non-peptidic and peptidicpyrimidinone compounds that act as an inhibitor of a coagulation factorpresent in the coagulation cascade or clotting process. In PCT PatentApplication WO 98/47876, Van Boeckel et al. describe peptidic6-alkylpyridones and 2-alkylpyrimidinones as anti-thrombotic compounds.In PCT Patent Application WO 98/16547, Zhu and Scarborough describe3-(N-heterocyclylamino)4,5,6-substituted-pyridonylacetamides and2,4-substituted-5-(N-heterocyclylamino)-pyrimidinonyl-acetamidescontaining amide substituents and having activity against mammalianfactor Xa. In U.S. Pat. No. 5,656,645, Tamura et al. describe4,5,6-substituted-3-aminopyridonyl-acetamides,1,6-substituted-5-aminouracinylacetamides, and2,4-substituted-5-aminopyrimidinonyl-acetamides containing amidesubstituents having a formyl function and having activity againstthrombin. In U.S. Pat. No. 5,658,930, Tamura et al. again describe4,5,6-substituted-3-aminopyridonyl-acetamides,1,6-substituted-5-aminouracinylacetamides, and2,4-substituted-5-aminopyrimidinonylacetamides containing amidesubstituents having a formyl function and having activity againstthrombin. In PCT Patent Applications 96/18644 and 97/46207, Tamura etal. further describe 4,5,6-substituted-3-aminopyridonylacetamides,1,6-substituted-5-aminouracinyl-acetamides, and2,4-substituted-5-aminopyrimidinonylacetamides containing amidesubstituents having a formyl function and having activity againstthrombin. In PCT Patent Application WO 98/09949, Suzuki et al. describe2-heterocyclylacetamido derivatives of 1,2-diketones and report thatthey inhibit proteases, especially chymase inhibitors.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide compounds that arebeneficial in anticoagulant therapy and that have a general structure:

It is another object of the present invention to provide methods forpreventing and treating thrombotic conditions, such as coronary arterydisease, cerebrovascular disease, and other coagulation relateddisorders. Such thrombotic conditions are prevented and treated byadministering to a patient in need thereof an effective amount ofcompounds of Formula (I).

Various other objects and advantages of the present invention willbecome apparent from the following description of the invention.

DESCRIPTION OF THE INVENTION

The present invention relates to a class of compounds comprisingSubstituted Polycyclic Aryl and Heteroaryl pyrimidinones, which arebeneficial in anticoagulant therapy for the treatment and prevention ofa variety of thrombotic conditions including coronary artery andcerebrovascular disease, as given in Formula (I):

or a pharmaceutically acceptable salt thereof, wherein;

J is selected from the group consisting of O and S;

J is optionally selected from the group consisting of CH—R⁶ and N—R⁶wherein R⁶ is a linear spacer moiety having a chain length of 1 to 4atoms linked to the point of bonding of a substituent selected from thegroup consisting of R^(4a), R^(4b), R³⁹, R⁴⁰, R⁵, R¹⁴, and R¹⁵ to form aheterocycyl; ring having 5 through 8 contiguous members;

J is optionally selected from the group consisting of CH—R⁶ and N—R⁶ R⁶is a linear spacer moiety having a chain length of 1 to 4 atoms linkedto the points of bonding of both R^(4a) and R^(4b) to form aheterocyclyl ring having 5 through 8 contiguous members;

J is optionally selected from the group consisting of CH—R⁶ and N—R⁶wherein R⁶ is a linear spacer moiety having a chain length of 1 to 4atoms linked to the points of bonding of both R³⁹ and R⁴⁰ to form aheterocyclyl ring having 5 through 8 contiguous members;

B is formula (V):

 wherein D¹, D², J¹, J² and K¹ are independently selected from the groupconsisting of C, N, O, S and a covalent bond with the provisos that nomore than one can be a covalent bond, no more than one of D¹, D², J¹, J²and K¹ is O, no more than one of D¹, D², J¹, J² and K¹ is S, one of D¹,D², J¹, J² and K¹ must be a covalent bond when two of D¹, D², J¹, J² andK¹ are O and S, and no more than four of D¹, D², J¹, J² and K¹ are Nwith the proviso that R³², R³³, R³⁴, R³⁵, and R³⁶ are each independentlyselected to maintain the tetravalent nature of carbon, trivalent natureof nitrogen, the divalent nature of sulfur, and the divalent nature ofoxygen;

R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R³², R³³, R³⁴, R³⁵, and R³⁶are independently selected from the group consisting of hydrido,acetamido, haloacetamido, amidino, guanidino, dialkylsulfonium,trialkylphosphonium, dialkylsulfoniumalkyl, carboxy, heteroaralkylthio,heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aryloylalkoxy,heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl,heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl,aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl,cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl,cycloalkylsulfonylalkyl, heteroarylamino,N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, haloalkylthio,alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy,cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy,cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl,hydroxy, amino, alkoxyamino, thio, nitro, lower alkylamino, alkylthio,alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl,heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl,arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl,heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl,haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido,alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkylamidosulfonyl, monoarylamidosulfonyl, arylsulfonamido,diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl,arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl,heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl,heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl,alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy,cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl,lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy,hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, alkylenylamnino,hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy,aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl,heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl,heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl,carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido,arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboxy,carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy,phosphono, phosphonoalkyl, diaralkoxyphosphono, anddiaralkoxyphosphonoalkyl;

R¹⁶, R¹⁹, R³², R³³, R³⁴, R³⁵, and R³⁶ are independently optionally Q^(b)with the proviso that no more than one of R¹⁶, and R¹⁹ is Q^(b) at thesame time and that Q^(b) is Q^(be);

R³², and R³³, R³³ and R³⁴, R³⁴ and R³⁵, and R³⁵ and R³⁶ areindependently optionally selected to form a spacer pair wherein a spacerpair is taken together to form a linear moiety having from 3 through 6contiguous atoms connecting the points of bonding of said spacer pairmembers to form a ring selected from the group consisting of acycloalkenyl ring having 5 through 8 contiguous members, a partiallysaturated heterocyclyl ring having 5 through 8 contiguous members, aheteroaryl ring having 5 through 6 contiguous members, and an aryl withthe proviso that no more than one of the group consisting of spacerpairs R³² and R³³, R³³ and R³⁴, R³⁴ and R³⁵, and R³⁵ and R³⁶ are used atthe same time;

R⁹ and R¹⁰, R¹⁰ and R¹¹, R¹¹ and R¹², and R¹² and R¹³ are independentlyoptionally selected to form a spacer pair wherein a spacer pair is takentogether to form a linear moiety having from 3 through 6 contiguousatoms connecting the points of bonding of said spacer pair members toform a ring selected from the group consisting of a cycloalkenyl ringhaving 5 through 8 contiguous members, a partially saturatedheterocyclyl ring having 5 through 8 contiguous members, a heteroarylring having 5 through 6 contiguous members, and an aryl with the provisothat no more than one of the group consisting of spacer pairs R⁹ andR¹⁰, R¹⁰ and R¹¹, R¹¹ and R¹², and R¹² R¹³ are used at the same time;

B is optionally formula (VI):

 wherein D³, D⁴, J³, and J⁴ are independently selected from the groupconsisting of C, N, O, and S, no more than one of D³, D⁴, J³, and J⁴ isO, no more than one of D³, D⁴, J³, and J⁴ is S, and no more than threeof D¹, D², J¹, and J² are N with the proviso that R³², R³³, R³⁴, and R³⁵are each independently selected to maintain the tetravalent nature ofcarbon, trivalent nature of nitrogen, the divalent nature of sulfur, andthe divalent nature of oxygen;

B is optionally selected from the group consisting of hydrido,trialkylsilyl, C2-C8 alkyl, C3-C8 alkenyl, C3-C8 alkylenyl, C3-C8alkynyl, C2-C8 haloalkyl, and C3-C8 haloalkenyl wherein each member ofgroup B is optionally substituted at any carbon up to and including 6atoms from the point of attachment of B to A with one or more of thegroup consisting of R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆;

B is optionally selected from the group consisting of C3-C15 cycloalkyl,C5-C10 cycloalkenyl, C4-C12 saturated heterocyclyl, and C4-C9 partiallysaturated heterocyclyl, wherein each ring carbon is optionallysubstituted with R³³, a ring carbon other than the ring carbon at thepoint of attachment of B to A is optionally substituted with oxoprovided that no more than one ring carbon is substituted by oxo at thesame time, ring carbon and nitrogen atoms adjacent to the carbon atom atthe point of attachment is optionally substituted with R⁹ or R¹³, a ringcarbon or nitrogen atom adjacent to the R⁹ position and two atoms fromthe point of attachment is optionally substituted with R¹⁰, a ringcarbon or nitrogen atom adjacent to the R¹³ position and two atoms fromthe point of attachment is optionally substituted with R¹², a ringcarbon or nitrogen atom three atoms from the point of attachment andadjacent to the R¹⁰ position is optionally substituted with R¹¹, a ringcarbon or nitrogen atom three atoms from the point of attachment andadjacent to the R¹² position is optionally substituted with R³³ and aring carbon or nitrogen atom four atoms from the point of attachment andadjacent to the R¹¹ and R³³ positions is optionally substituted withR³⁴;

A is selected from the group consisting of single covalent bond,(W⁷)_(rr)—(CH(R¹⁵))_(pa) and (CH(R¹⁵))_(pa)—(W⁷)_(rr) wherein rr is aninteger selected from 0 through 1, pa is an integer selected from 0through 6, and W⁷ is selected from the group consisting of O, S, C(O),C(S), C(O)S, C(S)O, C(O)N(R⁷), C(S)N(R⁷), (R⁷)NC(O), (R⁷)NC(S), S(O),S(O)₂, S(O)₂N(R⁷), (R⁷)NS(O)₂, Se(O), Se(O)₂, Se(O)₂N(R⁷), (R⁷)NSe(O)₂,P(O)(R⁸), N(R⁷)P(O)(R⁸), P(O)(R⁸)N(R⁷), C(NR⁷)N(R⁷), (R⁷)NC(NR⁷),(R⁷)NC(NR⁷)NR⁷, and N(R⁷) with the proviso that no more than one of thegroup consisting of rr and pa is 0 at the same time;

R⁷ and R⁸ are independently selected from the group consisting ofhydrido, hydroxy, alkyl, alkenyl, aryl, aralkyl, aryloxy, alkoxy,alkenyloxy, alkylthio, alkylamino, arylthio, arylamino, acyl, aroyl,heteroaroyl, aralkoxyalkyl, heteroaralkoxyalkyl, , aryloxyalkyl,alkoxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl,aralkoxyalkyl, heteroaralkoxyalkyl, alkylsulfinylalkyl,alkylsulfonylalkyl, heteroaryl, heteroaryloxy, heteroarylamino,heteroaralkyl, heteroaralkyloxy, heteroaralkylamino, andheteroaryloxyalkyl;

R¹⁴, R¹⁵, R³⁷, R³⁸, R³⁹, R⁴⁰, R⁴¹ and R² are independently selected fromthe group consisting of amidino, hydroxyamino, hydrido, hydroxy, halo,cyano, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl,aminoalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, sulfhydryl,acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl,aralkyl, aryloxyalkyl, aralkoxyalkylalkoxy, alkylsulfinylalkyl,alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl,alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl,arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl,cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl,halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl,saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl,heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl,monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl,haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl,arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl,cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl,heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl,carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl,carboaralkoxy, trialkylsilyl, dialkoxyphosphono, diaralkoxyphosphono,dialkoxyphosphonoalkyl, and diaralkoxyphosphonoalkyl with the provisothat R³⁷ and R³⁸ are independently selected from other than formyl and2-oxoacyl;

R¹⁴ and R¹⁴, when bonded to different carbons, are optionally takentogether to form a group selected from the group consisting of covalentbond, alkylene, haloalkylene, and a linear moiety spacer selected toform a ring selected from the group consisting of cycloalkyl ring havingfrom 5 through 8 contiguous members, cycloalkenyl ring having from 5through 8 contiguous members, and a heterocyclyl having from 5 through 8contiguous members;

R¹⁴ and R¹⁵, when bonded to different carbons, are optionally takentogether to form a group selected from the group consisting of covalentbond, alkylene, haloalkylene, and a linear moiety spacer selected toform a ring selected from the group consisting of a cycloalkyl ringhaving from 5 through 8 contiguous members, a cycloalkenyl ring havingfrom 5 through 8 contiguous members, and a heterocyclyl having from 5through 8 contiguous members;

R¹⁵ and R¹⁵, when bonded to different carbons, are optionally takentogether to form a group selected from the group consisting of covalentbond, alkylene, haloalkylene, and a linear moiety spacer selected toform a ring selected from the group consisting of cycloalkyl ring havingfrom 5 through 8 contiguous members, cycloalkenyl ring having from 5through 8 contiguous members, and a heterocyclyl having from 5 through 8contiguous members;

Ψ is selected from the group consisting of NR⁵, O, C(O), C(S), S, S(O),S(O)₂, ON(R⁵), P(O)(R⁸), and CR³⁹R⁴⁰;

R⁵ is selected from the group consisting of hydrido, hydroxy, amino,alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxy, aralkoxy, alkoxy,alkenyloxy, alkylthio, arylthio, aralkoxyalkyl, heteroaralkoxyalkyl,aryloxyalkyl, alkoxyalkyl, alkenyloxyalkyl, alkylthioalkyl,arylthioalkyl, aralkoxyalkyl, heteroaralkoxyalkyl, alkylsulfinylalkyl,alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl,cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl,halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl,halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, heteroaryl,heteroarylalkyl, monocarboalkoxyalkyl, monocarboalkoxy,dicarboalkoxyalkyl, monocarboxamido, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, anddialkoxyphosphonoalkyl;

R³⁹ and R⁴⁰, when bonded to the same carbon, are optionally takentogether to form a group selected from a group consisting of oxo,thiono, R⁵—N, alkylene, haloalkylene, and a linear moiety spacer havingfrom 2 through 7 contiguous atoms to form a ring selected from the groupconsisting of a cycloalkyl ring having from 3 through 8 contiguousmembers, a cycloalkenyl ring having from 3 through 8 contiguous members,and a heterocyclyl ring having from 3 through 8 contiguous members;

M is selected from the group consisting of N and R¹—C;

R² and R¹ are independently selected from the group consisting of Z⁰—Q,hydrido, alkyl, alkenyl, and halo;

R¹ is optionally selected from the group consisting of amino,aminoalkyl, alkylamino, amidino, guanidino, hydroxy, hydroxyamino,alkoxy, hydroxyalkyl, alkoxyamino, thiol, alkylthio, dialkylsulfonium,trialkylphosphonium, dialkylsulfoniumalkyl, heteroarylamino, nitro,arylamino, aralkylamino, alkanoyl, alkenoyl, aroyl, heteroaroyl,aralkanoyl, heteroaralkanoyl, haloalkanoyl, hydroxyhaloalkyl, cyano, andphosphono;

R² is optionally selected from the group consisting of amidino,guanidino, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl,heteroarylamino, amino, nitro, alkylamino, arylamino, aralkylamino,alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl,haloalkanoyl, hydroxyhaloalkyl, cyano, and phosphono;

R² and R^(4a), R² and R^(4b), R² and R¹⁴, and R² and R¹⁵ are optionallyindependently selected to form spacer pairs wherein a spacer pair istaken together to form a linear moiety having from 2 through 5contiguous atoms connecting the points of bonding of said spacer pairmembers to form a heterocyclyl ring having from 5 through 8 contiguousmembers with the proviso that no more than one of the group of spacerpairs consisting of R² and R^(4a), R² and R^(4b), R² and R¹⁴, and R² andR¹⁵ is used at the same time;

R² is optionally independently selected to form a linear moiety havingfrom 2 through 5 contiguous atoms linked to the points of bonding ofboth R^(4a) and R^(4b) to form a heterocyclyl ring having from 5 through8 contiguous members;

Z⁰ is selected from the group consisting of covalent single bond,(CR⁴¹R⁴²)_(q) wherein q is an integer selected from 1 through 6,(CH(R⁴¹))_(g)—W⁰—(CH(R⁴²))_(p) wherein g and p are integersindependently selected from 0 through 3 and W⁰ is selected from thegroup consisting of O, S, C(O), C(S), C(O)O, C(S)O, C(O)S, C(S)S,C(O)N(R⁴¹), (R⁴¹)NC(O), C(S)N(R⁴¹), (R⁴¹)NC(S), OC(O)N(R⁴¹),(R⁴¹)NC(O)O,SC(S)N(R⁴¹), (R⁴¹)NC(S)S, SC(O)N(R⁴¹), (R⁴¹)NC(O)S,OC(S)N(R⁴¹)(R⁴¹)NC(S)O, N(R⁴²)C(O)N(R⁴¹), (R⁴¹)NC(O)N(R⁴²),N(R⁴²)C(S)N(R⁴¹), (R⁴¹)NC(S)N(R⁴²), S(O), S(O)₂, S(O)₂N(R⁴¹),N(R⁴¹)S(O)₂, Se, Se(O), Se(O)₂, Se(O)₂N(R⁴¹), N(R⁴¹)Se(O)₂, P(O)(R⁸),N(R⁷)P(O)(R⁸), P(O)(R⁸)N(R⁷), N(R⁴¹), ON(R⁴¹), and SiR²⁸R²⁹, and(CH(R⁴¹))_(e)—W²²—(CH(R⁴²))_(h) wherein e and h are integersindependently selected from 0 through 2 and W²² is selected from thegroup consisting of CR⁴¹═CR⁴² CR⁴¹R⁴²═C; vinylidene), ethynylidene (C≡C;1,2-ethynyl), 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl,1,3-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl,2,4-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl,1,2-piperazinyl, 1,3-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl,1,2-piperidinyl, 1,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl,2,6-piperidinyl, 3,4-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl,2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl,2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, and3,4-tetrahydrofuranyl, with the provisos that R⁴¹ and R⁴² are selectedfrom other than halo and cyano when directly bonded to N and Z⁰ isdirectly bonded to the pyrimidinone ring;

R²⁸ and R²⁹ are independently selected from the group consisting ofhydrido, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, aralkyl,aryloxyalkyl, acyl, aroyl, aralkanoyl, heteroaroyl, aralkoxyalkyl,alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl,heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl,alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl,cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl,haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl,haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl,perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl,heteroarylthioalkyl, heteroaralkylthioalkyl, cyanoalkyl, dicyanoalkyl,carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl,carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl,dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl,carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl,dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, arylsulfinylalkyl,arylsulfonylalkyl, aralkylsulfinyl, cycloalkylsulfinylalkyl,cycloalkylsufonylalkyl, heteroarylsulfonylalkyl,heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl,carboxy, dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyland diaralkoxyphosphonoalkyl;

R²⁸ and R²⁹ are optionally taken together to form a linear moiety spacerhaving from 2 through 7 contiguous atoms and forming a ring selectedfrom the group consisting of a cycloalkyl ring having from 3 through 8contiguous members, a cycloalkenyl ring having from 3 through 8contiguous members, and a heterocyclyl ring having from 3 through 8contiguous members;

Q is formula (II):

 wherein D¹, D², J¹, J² and K¹ are independently selected from the groupconsisting of C, N, O, S and a covalent bond with the provisos that nomore than one can be a covalent bond, no more than one of D¹, D², J¹, J²and K¹ can be O, no more than one of D¹, D², J¹, J² and K¹ can be S, oneof D¹, D², J¹, J² and K¹ must be a covalent bond when two of D¹, D², J¹,J² and K¹ are O and S, and no more than four of D¹, D², J¹, J² and K¹can be N, with the proviso that R⁹, R¹⁰, R¹¹, R¹², and R¹³ are eachindependently selected to maintain the tetravalent nature of carbon,trivalent nature of nitrogen, the divalent nature of sulfur, and thedivalent nature of oxygen;

Q is optionally selected from formula (III):

 wherein D³, D⁴, J³, and J⁴ are independently selected from the groupconsisting of C, N, O, and S, no more than one of D³, D⁴, J³, and J⁴ isO, no more than one of D³, D⁴, J³, and J⁴ is S, and no more than threeof D¹, D², J¹, and J² are N with the proviso that R⁹, R¹⁰, R¹¹, and R¹²are each independently selected to maintain the tetravalent nature ofcarbon, trivalent nature of nitrogen, the divalent nature of sulfur, andthe divalent nature of oxygen;

Q is optionally selected from the group consisting of hydrido, alkyl,alkoxy, alkylamino, alkylthio, haloalkylthio, alkenyl, alkynyl,saturated heterocyclyl, partially saturated heterocyclyl, acyl, aroyl,heteroaroyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,cycloalkenylalkyl, cycloalkylalkenyl, haloalkyl, haloalkoxy,haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl,haloalkenyloxyalkyl, halocycloalkoxyalkyl, and halocycloalkenyloxyalkylwith the proviso that Z is selected from other than a single covalentbond when Q is hydrido;

K is (CR^(4a)R^(4b))_(n) wherein n is an integer selected from 1 through4;

R^(4a) and R^(4b) are independently selected from the group consistingof halo, hydrido, hydroxy, cyano, hydroxyalkyl, alkyl, alkenyl, aryl,aralkyl, aralkoxyalkyl, aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl,alkenyloxyalkyl, alkylthioalkyl, aralkylthioalkyl, arylthioalkyl,cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl, heteroaryl,heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl,cyanoalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, haloalkylsulfinyl,arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfonylalkyl,heteroarylsulfinylalkyl, aralkylsulfinylalkyl, and aralkylsulfonylalkylwith the provisos that halo, hydroxy, and cyano are bonded to differentcarbons when simultaneously present and that R^(4A) and R^(4b) are otherthan hydroxy or cyano when bonded to the carbon directly bonded to thepyrimidinone nitrogen;

R^(4a) and R^(4b), when bonded to the same carbon, are optionally takentogether to form a group selected from the group consisting of oxo,thiono, and a linear spacer moiety having from 2 through 7 contiguousatoms connected to form a ring selected from the group consisting of acycloalkyl ring having 3 through 8 contiguous members, a cycloalkenylring having 5 through 8 contiguous members, and a heterocyclyl ringhaving 5 through 8 contiguous members with the proviso that R^(4a) andR^(4b) taken together is other than oxo or thiono when the common carbonis directly bonded to the pyrimidinone nitrogen;

E⁰ is E¹ when K is (CR^(4a)R^(4b))_(n), wherein E¹ is selected from thegroup consisting of a covalent single bond, O, S, C(O), C(S), C(O)O,C(S)O, C(O)S, C(S)S, C(O)N(R⁷), (R⁷)NC(O), C(S)N(R⁷), (R⁷)NC(S),OC(O)N(R⁷), (R⁷)NC(O)O, SC(S)N(R⁷), (R⁷)NC(S)S, SC(O)N(R⁷), (R⁷)NC(O)S,OC(S)N(R⁷), (R⁷)NC(S)O, N(R⁸)C(O)N(R⁷), (R⁷)NC(O)N(R⁸), N(R⁸)C(S)N(R⁷),(R⁷)NC(S)N(R⁸), S(O), S(O)₂, S(O)₂N(R⁷), N(R⁷)S(O)₂, S(O)₂N(R⁷)C(O),C(O)N(R⁷)S(O)₂, Se, Se(O), Se(O)₂, Se(O)₂N(R⁷), N(R⁷)Se(O)₂, P(O)(R⁸),N(R⁷)P(O)(R⁸), P(O)(R⁸)N(R⁷), N(R⁷), ON(R⁷), SiR²⁸R²⁹, CR^(4a)═CR^(4b),ethynylidene (C≡C; 1,2-ethynyl), and C═CR^(4a)R^(4b);

K is optionally selected to be (CH(R¹⁴))_(j)—T wherein j is selectedfrom a integer from 0 through 3 and T is selected from the groupconsisting of single covalent bond, O, S, and N(R⁷) with the provisosthat R¹⁴ is other than hydroxy, cyano, halo, amino, alkylamino,dialkylamino, and sulfhydryl when j is 1 and that (CH(R¹⁴))_(j) isbonded to the pyrimidinone ring;

E⁰ is optionally E², when K is (CH(R¹⁴))_(j)—T, wherein E² is selectedfrom the group consisting of a covalent single bond, C(O), C(S), C(O)O,C(S)O, C(O)S, C(S)S, C(O)N(R⁷), (R⁷)NC(O), C(S)N(R⁷), (R⁷)NC(S),(R⁷)NC(O)O, (R⁷)NC(S)S, (R⁷)NC(O)S, (R⁷)NC(S)O,N(R⁸)C(O)N(R⁷),(R⁷)NC(O)N(R⁸), N(R⁸)C(S)N(R⁷), (R⁷)NC(S)N(R⁸), S(O), S(O)₂, S(O)₂N(R⁷),N(R⁷)S(O)₂, S(O)₂N(H)C(O), C(O)N(H)S(O)₂, Se(O), Se(O)₂, Se(O)₂N(R⁷),N(R⁷)Se(O)₂, P(O)(R⁸), N(R⁷)P(O)(R⁸), P(O)(R⁸)N(R⁷), and N(R⁷);

K is optionally selected to be G—(CH(R¹⁵))_(k) wherein k is selectedfrom an integer from 1 through 3 and G is selected from the groupconsisting of O, S, and N(R⁷) with the proviso that R¹⁵ is other thanhydroxy, cyano, halo, amino, alkylamino, dialkylamino, and sulfhydrylwhen k is 1;

E⁰ is optionally E³ when K is G—(CH(R¹⁵))_(k) wherein E³ is selectedfrom the group consisting of a covalent single bond, O, S, C(O), C(S),C(O)O, C(S)O, C(O)S, C(S)S, C(O)N(R⁷), (R⁷)NC(O), C(S)N(R⁷), (R⁷)NC(S),OC(O)N(R⁷), (R⁷)NC(O)O, SC(S)N(R⁷), (R⁷)NC(S)S, SC(O)N(R⁷), (R⁷)NC(O)S,OC(S)N(R⁷), (R⁷)NC(S)O, N(R⁸)C(O)N(R⁷), (R⁷)NC(O)N(R⁸), N(R⁸)C(S)N(R⁷),(R⁷)NC(S)N(R⁸), S(O), S(O)₂, S(O)₂N(R⁷), N(R⁷)S(O)₂, Se, Se(O), Se(O)₂,Se(O)₂N(R⁷), N(R⁷)Se(O)₂, P(O)(R⁸), N(R⁷)P(O)(R⁸), P(O)(R⁸)N(R⁷), N(R⁷),ON(R⁷), SiR²⁸R²⁹, CR^(4a)═CR^(4b), ethynylidene (C≡C; 1,2-ethynyl), andC═CR^(4a)R^(4b);

Y⁰ is formula (IV):

 wherein D⁵, D⁶, J⁵, and J⁶ are independently selected from the groupconsisting of C, N, O, S and a covalent bond with the provisos that nomore than one is a covalent bond, K² is independently selected from thegroup consisting of C and N⁺, no more than one of D⁵, D⁶, J⁵, and J⁶ isO, no more than one of D⁵, D⁶, J⁵, and J⁶ is S, one of D⁵, D⁶, J⁵, andJ⁶ must be a covalent bond when two of D⁵, D⁶, J⁵, and J⁶ are O and S,no more than three of D⁵, D⁶, J⁵, and J⁶ are N when K² is N⁺, and nomore than four of D⁵, D⁶, J⁵, and J⁶ are N when K² is carbon with theprovisos that R¹⁶, R¹⁷, R¹⁸, and R¹⁹ are each independently selected tomaintain the tetravalent nature of carbon, trivalent nature of nitrogen,the divalent nature of sulfur, and the divalent nature of oxygen;

R¹⁶ and R¹⁷ are independently optionally taken together to form a linearmoiety spacer having from 3 through 6 contiguous atoms connected to forma ring selected from the group consisting of a cycloalkenyl ring havingfrom 5 through 8 contiguous members, a partially saturated heterocyclylring having from 5 through 8 contiguous members, a heteroaryl havingfrom 5 through 6 contiguous members, and an aryl;

R¹⁸ and R¹⁹ are independently optionally taken together to form a linearmoiety spacer having from 3 through 6 contiguous atoms connected to forma ring selected from the group consisting of a cycloalkenyl ring havingfrom 5 through 8 contiguous members, a partially saturated heterocyclylring having from 5 through 8 contiguous members, a heteroaryl havingfrom 5 through 6 contiguous members, and an aryl;

Q^(b) is selected from the group consisting of NR²⁰R²¹, ⁺NR²⁰R²¹R²²,oxy, alkyl, aminoalkylenyl, alkylamino, dialkylamino,dialkylsulfoniumalkyl, acylamino and Q^(be) wherein Q^(be) is hydridoand R²⁰, R²¹, and R²² are independently selected from the groupconsisting of hydrido, amino, alkyl, hydroxy, alkoxy,aminoalkylenyl,alkylamino, dialkylamino, and hydroxalkyl with theprovisos that no more than one of R²⁰, R²¹, and R²² is hydroxy, alkoxy,alkylamino, amino, and dialkylamino at the same time and that R²⁰, andR²¹, and R²² must be other than be hydroxy, alkoxy, alkylamino, amino,and dialkylamino when K² is N⁺;

R²⁰ and R²¹, R²⁰ and R²², and R²¹ and R²² are independently optionallyselected to form a spacer pair wherein a spacer pair is taken togetherto form a linear moiety having from 4 through 7 contiguous atomsconnecting the points of bonding of said spacer pair members to form aheterocyclyl ring having 5 through 8 contiguous members with the provisothat no more than one of the group consisting of spacer pairs R²⁰ andR²¹, R²⁰ and R²², and is used at the same time;

Q^(b) is optionally selected from the group consisting ofN(R²⁶)SO₂N(R²³)(R²⁴), N(R²⁶)C(O)OR⁶, N(R²⁶)C(O)SR⁵, N(R²⁶)C(S)OR⁵ andN(R²⁶)C(S)SR⁵ with the proviso that no more than one of R²³, R²⁴, andR²⁶ can be hydroxy, alkoxy, alkyleneamino, alkylamino, amino, ordialkylamino when two of the group consisting of R²³, R²⁴, and R²⁶ arebonded to the same atom;

Q^(b) is optionally selected from the group consisting ofdialkylsulfonium, trialkylphosphonium, C(NR²⁵)NR²³R²⁴,N(R²⁶C(NR²⁵)N(R²³)(R²⁴), N(R²⁶)C(O)N(R²³)(R²⁴), N(R²⁶)C(S)N(R²³)(R²⁴),C(NR²⁵)OR⁵, C(O)N(R²⁶)C(NR²⁵)N(R²³)(R²⁴), C(S)N(R²⁶)C(NR²⁵)N(R²³)(R²⁴),N(R²⁶)N(R²⁶)C(NR²⁵)N(R²³)(R²⁴), ON(R²⁶)C(NR²⁵)N(R²³)(R²⁴),N(R²⁶)N(R²⁶)SO₂N(R²³)(R²⁴), C(NR²⁵)SR⁵, C(O)NR²³R²⁴, and C(O)NR²³R²⁴with the provisos that no more than one of R²³, R²⁴, and R²⁶ can behydroxy, alkoxy, alkylamino, amino, or dialkylamino when any two of thegroup consisting of R²³, R²⁴, and R²⁶ are bonded to the same atom andthat said Q^(b) group is bonded directly to a carbon atom;

R²³, R²⁴, R²⁵, and R²⁶ are independently selected from the groupconsisting of hydrido, alkyl, hydroxy, alkoxy, alkylenylamino, amino,alkylamino, dialkylamino, and hydroxyalkyl;

R²³ and R²⁴ are optionally taken together to form a linear spacer moietyhaving from 4 through 7 contiguous atoms connecting the points ofbonding to form a heterocyclyl ring having 5 through 8 contiguousmembers;

R²³ and R²⁵, R²⁴ and R²⁵, R²⁵ and R²⁶, R²⁴ and R²⁶, and R²³ and R²⁶ areindependently optionally selected to form a spacer pair wherein a spacerpair is taken together from the points of bonding of selected spacerpair members to form the group L—U—V wherein L, U, and V areindependently selected from the group consisting of O, S, C(O), C(S),C(J_(H))₂S(O), SO₂, OP(OR³¹)R³⁰, P(O)R³⁰, P(S)R³⁰, C(R³⁰)R³¹,C═C(R³⁰)R³¹, (O)₂POP(O)₂, R³⁰(O)POP(O)R³⁰, Si(R²⁹)R²⁸,Si(R²⁹)R²⁸Si(R²⁹)R^(28, Si(R) ²⁹)R²⁸OSi(R²⁹)R²⁸, (R²⁸)R²⁹COC(R²⁸)R²⁹,(R²⁸)R²⁹CSC(R²⁸)R²⁹, C(O)C(R³⁰)═C(R³¹), C(S)C(R³⁰)═C(R³¹),S(O)C(R³⁰)═C(R³¹), SO₂C(R³⁰)═C(R³¹), PR³⁰C(R³⁰)═C(R³¹),P(O)R³⁰C(R³⁰)═C(R³), P(S)R³⁰C(R³⁰)═C(R³¹), DC(R³⁰)(R³)D, OP(OR³)R³⁰,P(O)R³⁰, P(S)R³⁰, Si(R²⁸)R and N(R²⁹), N(R³⁰), and a covalent bond withthe proviso that no more than any two of L, U and V are simultaneouslycovalent bonds and the heterocyclyl comprised of by L, U, and V has from5 through 10 contiguous member;

D is selected from the group consisting of oxygen, C═O, C═S, S(O)_(m)wherein m is an integer selected from 0 through 2;

J_(H) is independently selected from the group consisting of OR²⁷, SR²⁷and N(R²⁰)R²¹;

R²⁷ is selected from the group consisting of hydrido, alkyl, alkenyl,alkynyl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl,alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl,alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl,arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl,cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl,halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl,halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryloxyalkyl,heteroaryl, heteroarylalkyl, heteroarylthioalkyl,heteroaralkylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl,cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,heteroarylsulfonylalkyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyland aralkylsulfonylalkyl;

R³⁰ and R³¹ are independently selected from the group consisting ofhydrido, hydroxy, thiol, aryloxy, amino, alkylamino, dialkylamino,hydroxyalkyl, heteroaryloxyalkyl, alkoxy, alkylthio, arylthio, alkyl,alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl,alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl,heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl,alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl,cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl,haloalkyl, haloalkenyl, haloaralkylsulfinylalkyl, aralkylsulfonylalkyl,cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl,cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl,cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl,dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl,carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl,dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl,dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy,dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino,phosphonoalkylaraino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl,sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl,alkoxysulfonylalkoxy, aralkoxysulfonylalkoxy, sulfonylalkoxy,alkoxysulfonylalkylamino, aralkoxysulfonylalkylaamino, andsulfonylalkylamino;

R³⁰ and R³¹ are optionally taken to form a linear moiety spacer grouphaving from 2 through 7 contiguous atoms to form a ring selected fromthe group consisting of a cycloalkyl ring having from 3 through 8contiguous members, a cycloalkenyl ring having from 3 through 8contiguous members, and a heterocyclyl ring having from 3 through 8contiguous members;

R²³ and R²⁵, R²⁴ and R²⁵, R²⁵ and R²⁶, R²⁴ and R²⁶, and R²³ and R²⁶ areindependently optionally selected to form a spacer pair wherein a spacerpair is taken together from the points of bonding of selected spacerpair members to form the group L—U—V wherein L, U, and V areindependently selected from the group of 1,2-disubstituted radicalsconsisting of a cycloalkyl radical, a cycloalkenyl radical whereincycloalkyl and cycloalkenyl radicals are substituted with one or moregroups selected from R³⁰ and R³¹, an aryl radical, an heteroarylradical, a saturated heterocyclic radical and a partially saturatedheterocyclic radical wherein said 1,2-substitutents are independentlyselected from C═O, C═S, C(R²⁸)R³² SO), S(O)₂, OP(OR³¹)R³⁰, P(O)R³⁰,P(S)R³⁰ and Si(R²⁸)R²⁹;

R²³ and R₂₅, R²⁴ and R²⁵, R²⁵ and R²⁶, R²⁴ and R²⁶, and R²³ and R²⁶ areindependently optionally selected to form a spacer pair wherein a spacerpair is taken together from the points of bonding of selected spacerpair members to form the group L—U—V wherein L, U, and V areindependently selected from the group of radicals consisting of1,2-disubstituted alkylene radicals and 1,2-disubstituted alkenyleneradical wherein said 1,2-substitutents are independently selected fromC═O, C═S, C(R²⁸)R²⁹, S(O), S(O)₂, OP(OR³¹)R³⁰, P(O)R³⁰, P(S)R³⁰, andSi(R²⁸)R²⁹ and said alkylene and alkenylene radical are substituted withone or more R³⁰ or R³¹ substituents;

Q^(s) is selected from the group consisting of a single covalent bond,(CR³⁷R³⁸)_(b)—(W⁰)_(az) wherein az is an integer selected from 0 through1, b is an integer selected from 1 through 4, and W⁰ is selected fromthe group consisting of O, S, C(O), C(S), C(O)O, C(S)O, C(O)S, C(S)S,C(O)N(R¹⁴), (R¹⁴)NC(O), C(S)N(R¹⁴), (R¹⁴)NC(S), OC(O)N(R¹⁴),SC(S)N(R¹⁴), SC(O)N(R¹⁴), OC(S)N(R¹⁴), N(R¹⁵)C(O)N(R¹⁴),(R¹⁴)NC(O)N(R¹⁵), N(R¹⁵)C(S)N(R¹⁴), (R¹⁴)NC(S)N(R¹⁵), S(O), S(O)₂,S(O)₂N(R¹⁴), N(R¹⁴)S(O)₂, Se, Se(O), Se(O)₂, Se(O)₂N(R¹⁷), N(R¹⁴)Se(O)₂,P(O)(R⁸), N(R⁷)P(O)(R⁸), P(O)(R⁸)N(R⁷), N(R¹⁴), ON(R¹⁴), and SiR²⁸R²⁹,(CH(R¹⁴))_(c)—W¹—(CH(R¹⁵))_(d) wherein c and d are integersindependently selected from 1 through 4, and W¹ is selected from thegroup consisting of O, S, C(O), C(S), C(O)O, C(S)O, C(O)S, C(S)S,C(O)N(R¹⁴), (R¹⁴)NC(O), C(S)N(R¹⁴), (R¹⁴)NC(S), OC(O)N(R¹⁴),(R¹⁴)NC(O)O, SC(S)N(R¹⁴), (R¹⁴)NC(S)S, SC(O)N(R¹⁴), (R¹⁴)NC(O)S,OC(S)N(R¹⁴), (R¹⁴)NC(S)O, N(R¹⁵)C(O)N(R¹⁴), (R¹⁴)NC(O)N(R¹⁵),N(R¹⁵)C(S)N(R¹⁴), (R¹⁴)NC(S)N(R¹⁵), S(O), S(O)₂, S(O)₂N(R¹⁴),N(R¹⁴)S(O)₂, Se, Se(O), Se(O)₂, Se(O)₂N(R¹⁴), N(R¹⁴)Se(O)₂, P(O)(R⁸),N(R⁷)P(O)(R⁸), P(O)(R⁸)N(R⁷), N(R¹⁴), ON(R¹⁴), SiR²⁸R²⁹, and(CH(R¹⁴))_(e)—W²²—(CH(R¹⁵))_(h) wherein e and h are integersindependently selected from 0 through 2 and W²² is selected from thegroup consisting of CR⁴¹═CR⁴², CR⁴¹R⁴²═C; vinylidene), ethynylidene(C≡C; 1,2-ethynyl), 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl,1,3-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl,2,4-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl,1,2-piperazinyl, 1,3-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl,1,2-piperidinyl, 1,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl,2,6-piperidinyl, 3,4-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl,2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl,2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, and3,4-tetrahydrofuranyl, with the provisos that R¹⁴ and R¹⁵ are selectedfrom other than halo and cyano when directly bonded to N and that(CR³⁷R³⁸)_(b), (CH(R¹⁴))_(c), (CH(R¹⁴))_(e) and are bonded to E⁰;

R³⁷ and R³⁷, when bonded to different carbons, are optionally takentogether to form a linear moiety spacer having from 1 through 7contiguous atoms to form a ring selected from the group consisting of acycloalkyl ring having from 3 through 8 contiguous members, acycloalkenyl ring having from 3 through 8 contiguous members, and aheterocyclyl ring having from 3 through 8 contiguous members;

R³⁷ and R³⁸, when bonded to different carbons, are taken together toform a linear moiety spacer having from 1 through 7 contiguous atoms toform a ring selected from the group consisting of a cycloalkyl ringhaving from 3 through 8 contiguous members, a cycloalkenyl ring havingfrom 3 through 8 contiguous members, and a heterocyclyl ring having from3 through 8 contiguous members;

R³⁸ and R³⁸, when bonded to different carbons, are taken together toform a linear moiety spacer having from 1 through 7 contiguous atoms toform a ring selected from the group consisting of a cycloalkyl ringhaving from 3 through 8 contiguous members, a cycloalkenyl ring havingfrom 3 through 8 contiguous members, and a heterocyclyl ring having from3 through 8 contiguous members;

R³⁷ and R³⁸, when bonded to the same carbon, are taken together to forma group selected from a group consisting of oxo, thiono, alkylene,haloalkylene, and a linear moiety spacer having from 2 through 7contiguous atoms to form a ring selected from the group consisting of acycloalkyl ring having from 3 through 8 contiguous members, acycloalkenyl ring having from 3 through 8 contiguous members, and aheterocyclyl ring having from 3 through 8 contiguous members;

Y⁰ is optionally Q^(b)—Q^(ss) wherein Q^(ss) is selected from the groupconsisting of (CR³⁷R³⁸)_(f) wherein f is an integer selected from 1through 6, (CH(R¹⁴))_(c)—W—(CH(R¹⁵))_(d) wherein c and d are integersindependently selected from 1 through 4, and W¹ is selected from thegroup consisting of W¹ is selected from the group consisting of O, S,C(O), C(S), C(O)O, C(S)O, C(O)S, C(S)S, C(O)N(R¹⁴), (R¹⁴)NC(O),C(S)N(R¹⁴), (R¹⁴)NC(S), OC(O)N(R¹⁴), (R¹⁴)NC(O)O, SC(S)N(R¹⁴),(R¹⁴)NC(S)S, SC(O)N(R¹⁴), (R¹⁴)NC(O)S, OC(S)N(R¹⁴), (R¹⁴)NC(S)O,N(R¹⁵)C(O)N(R¹⁴), (R¹⁴)NC(O)N(R¹⁵), N(R¹⁵)C(S)N(R¹⁴) (R¹⁴)NC(S)N(R¹⁵,S(O), S(O)₂, S(O)₂N(R¹⁴), N(R¹⁴)S(O)₂, Se, Se(O), Se(O)₂, Se(O)₂N(R¹⁴),N(R¹⁴)Se(O)2, P(O)(R⁸), N(R⁷)P(O)(R⁸), P(O)(R⁸)N(R⁷), N(R¹⁴), ON(R¹⁴),SiR²⁸R²⁹, and (CH(R¹⁴))_(e)—W²—(CH(R¹⁵))_(h) wherein e and h areintegers independently selected from 0 through 2 and W² is selected fromthe group consisting of CR^(4a)═CR^(4b), ethynylidene (C≡C;1,2-ethynyl), and C═CR^(4a)R^(4b) with the provisos that R¹⁴ and R¹⁵ areselected from other than halo and cyano when directly bonded to N, that(CR³⁷R³⁸)_(f), (CH(R¹⁵))_(c), and (CH(R¹⁵))_(e) are bonded to E⁰, andQ^(b) is selected from other than N(R²⁶)N(R²⁶)C(NR²⁵)N(R²³)(R²⁴) orON(R²⁶)C(NR²⁵)N(R²³)(R²⁴) when Q^(ss) is (CR³⁷R³⁸)_(f) wherein f isother than the integer 1;

Y⁰ is optionally Q^(b)—Q^(sss) wherein Q^(sss) is (CH(R³⁸))_(r)—W³, r isan integer selected from 1 through 3, W³ is selected from the groupconsisting of 1,1-cyclopropyl, 1,2-cyclopropyl, 1,1-cyclobutyl,1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl,1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl,2,5-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl,1,2-piperazinyl, 1,3-piperazinyl, 1,4-piperazinyl, 2,3-piperazinyl,2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl,1,4-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,5-piperidinyl,2,6-piperidinyl, 3,4-piperidinyl, 3,5-piperidinyl, 3,6-piperidinyl,1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl,2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2H-2,3-pyranyl, 2H-2,4-pyranyl,2H-2,5-pyranyl, 4H-2,3-pyranyl, 4H-2,4-pyranyl, 4H-2,5-pyranyl,2H-pyran-2-one-3,4-yl, 2H-pyran-2-one-4,5-yl, 4H-pyran-4-one-2,3-yl,2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl,3,4-tetrahydrofuranyl, 2,3-tetrahydropyranyl, 2,4-tetrahydropyranyl,2,5-tetrahydropyranyl, 2,6-tetrahydropyranyl, 3,4-tetrahydropyranyl, and3,5-tetrahydropyranyl, and each carbon and hyrido containing nitrogenmember of the ring of the W³ other than the points of attachment isoptionally substituted with one or more of the group consisting of R⁹,R¹⁰, R¹¹, and R¹², with the proviso that (CH(R³⁸))_(r) is bonded to E⁰and Q^(b) is bonded to lowest numbered substituent position of each W³;

Y⁰ is optionally Q^(b)—Q^(sssr) wherein Q^(sssr) is (CH(R³⁸))_(r)—W⁴, ris an integer selected from 1 through 3, W⁴ is selected from the groupconsisting of 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl,1,4-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl,2,4-morpholinyl, 2,5-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl,3,5-morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 1,4-piperazinyl,2,3-piperazinyl, 2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl,1,3-piperidinyl, 1,4-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl,2,5-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 3,5-piperidinyl,3,6-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl,2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2H-2,3-pyranyl,2H-2,4-pyranyl, 2H-2,5-pyranyl, 4H-2,3-pyranyl, 4H-2,4-pyranyl,4H-2,5-pyranyl, 2H-pyran-2-one-3,4-yl, 2H-pyran-2-one-4,5-yl,4H-pyran-4-one-2,3-yl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl,2,5-tetrahydrofuranyl, 3,4-tetrahydrofuranyl, 2,3-tetrahydropyranyl,2,4-tetrahydropyranyl, 2,5-tetrahydropyranyl, 2,6-tetrahydropyranyl,3,4-tetrahydropyranyl, and 3,5-tetrahydropyranyl, and each carbon andhydrido containing nitrogen member of the ring of the W⁴ other than thepoints of attachment is optionally substituted with one or more of thegroup consisting of R⁹, R¹⁰, R¹¹, and R¹², with the provisos that(CH(R³⁸))_(r) is bonded to E⁰ and Q⁶ is bonded to highest numbersubstituent position of each W⁴;

Y⁰ is optionally Q^(b)—Q^(ssss) wherein Q^(ssss) is (CH(R³⁸)_(r)—W⁵, ris an integer selected from 1 through 3, W⁵ is selected from the groupconsisting of 1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7-indenyl,2,7-indenyl, 2,6-indenyl, 2,5-indenyl, 2,4-indenyl, 3,4-indenyl,3,5-indenyl, 3,6-indenyl, 3,7-indenyl, 2,4-benzofuranyl,2,5-benzofuranyl, 2,6-benzofuranyl, 2,7-benzofuranyl, 3,4-benzofuranyl,3,5-benzofuranyl, 3,6-benzofuranyl, 3,7-benzofuranyl,2,4-benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl,2,7-benzothiophenyl, 3,4-benzothiophenyl, 3,5-benzothiophenyl,3,6-benzothiophenyl, 3,7-benzothiophenyl, 2,4-imidazo(1,2-a)pyridinyl,2,5-imidazo(1,2-a)pyridinyl, 2,6-imidazo(1,2-a)pyridinyl,2,7-imidazo(1,2-a)pyridinyl, 3,4-imidazo(1,2-a)pyridinyl,3,5-imidazo(1,2-a)pyridinyl, 3,6-imidazo(1,2-a)pyridinyl,3,7-imidazo(1,2-a)pyridinyl, 2,4-indolyl, 2,5-indolyl, 2,6-indolyl,2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6-indolyl, 3,7-indolyl,1,4-isoindolyl, 1,5-isoindolyl, 1,6-isoindolyl, 2,4-isoindolyl,2,5-isoindolyl, 2,6-isoindolyl, 2,7-isoindolyl, 1,3-isoindolyl,3,4-indazolyl, 3,5-indazolyl, 3,6-indazolyl, 3,7-indazolyl,2,4-benzoxazolyl, 2,5-benzoxazolyl, 2,6-benzoxazolyl, 2,7-benzoxazolyl,3,4-benzisoxazolyl, 3,5-benzisoxazolyl, 3,6-benzisoxazolyl,3,7-benzisoxazolyl, 1,4-naphthyl, 1,5-naphthyl, 1,6-naphthyl,1,7-naphthyl, 1,8-naphthyl, 2,4-naphthyl, 2,5-naphthyl, 2,6-naphthyl,2,7-naphthyl, 2,8-naphthyl, 2,4-quinolinyl, 2,5-quinolinyl,2,6-quinolinyl, 2,7-quinolinyl, 2,8-quinolinyl, 3,4-quinolinyl,3,5-quinolinyl, 3,6-quinolinyl, 3,7-quinolinyl, 3,8-quinolinyl,4,5-quinolinyl, 4,6-quinolinyl, 4,7-quinolinyl, 4,8-quinolinyl,1,4-isoquinolinyl, 1,5-isoquinolinyl, 1,6-isoquinolinyl,1,7-isoquinolinyl, 1,8-isoquinolinyl, 3,4-isoquinolinyl,3,5-isoquinolinyl, 3,6-isoquinolinyl, 3,7-isoquinolinyl,3,8-isoquinolinyl, 4,5-isoquinolinyl, 4,6-isoquinolinyl,4,7-isoquinolinyl, 4,8-isoquinolinyl, 3,4-cinnolinyl, 3,5-cinnolinyl,3,6-cinnolinyl, 3,7-cinnolinyl, 3,8-cinnolinyl, 4,5-cinnolinyl,4,6-cinnolinyl, 4,7-cinnolinyl, and 4,8-cinnolinyl, and each carbon andhydrido containing nitrogen member of the ring of the W⁵ other than thepoints of attachment is optionally substituted with one or more of thegroup consisting of R⁹, R¹⁰, R¹¹, and R¹², with the proviso that Q^(b)is bonded to lowest number substituent position of each W⁵ and that(CH(R³⁸))_(r) is bonded to E⁰;

Y⁰ is optionally Q^(b)—Q^(ssssr) wherein Q^(ssssr) is (CH(R³⁸))_(r)—W⁶,r is an integer selected from 1 through 3, W⁶ is selected from the groupconsisting of 1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7-indenyl,2,7-indenyl, 2,6-indenyl, 2,5-indenyl, 2,4-indenyl, 3,4-indenyl,3,5-indenyl, 3,6-indenyl, 3,7-indenyl, 2,4-benzofuranyl,2,5-benzofuranyl, 2,6-benzofuranyl, 2,7-benzofuranyl, 3,4-benzofuranyl,3,5-benzofuranyl, 3,6-benzofuranyl, 3,7-benzofuranyl,2,4-benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl,2,7-benzothiophenyl, 3,4-benzothiophenyl, 3,5-benzothiophenyl,3,6-benzothiophenyl, 3,7-benzothiophenyl, 2,4-imidazo(1,2-a)pyridinyl,2,5-imidazo(1,2-a)pyridinyl, 2,6-imidazo(1,2-a)pyridinyl,2,7-imidazo(1,2-a)pyridinyl, 3,4-imidazo(1,2-a)pyridinyl,3,5-imidazo(1,2-a)pyridinyl, 3,6-imidazo(1,2-a)pyridinyl,3,7-imidazo(1,2-a)pyridinyl, 2,4-indolyl, 2,5-indolyl, 2,6-indolyl,2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6-indolyl, 3,7-indolyl,1,4-isoindolyl, 1,5-isoindolyl, 1,6-isoindolyl, 2,4-isoindolyl,2,5-isoindolyl, 2,6-isoindolyl, 2,7-isoindolyl, 1,3-isoindolyl,3,4-indazolyl, 3,5-indazolyl, 3,6-indazolyl, 3,7-indazolyl,2,4-benzoxazolyl, 2,5-benzoxazolyl, 2,6-benzoxazolyl, 2,7-benzoxazolyl,3,4-benzisoxazolyl, 3,5-benzisoxazolyl, 3,6-benzisoxazolyl,3,7-benzisoxazolyl, 1,4-naphthyl, 1,5-naphthyl, 1,6-naphthyl,1,7-naphthyl, 1,8-naphthyl, 2,4-naphthyl, 2,5-naphthyl, 2,6-naphthyl,2,7-naphthyl, 2,8-naphthyl, 2,4-quinolinyl, 2,5-quinolinyl,2,6-quinolinyl, 2,7-quinolinyl, 2,8-quinolinyl, 3,4-quinolinyl,3,5-quinolinyl, 3,6-quinolinyl, 3,7-quinolinyl, 3,8-quinolinyl,4,5-quinolinyl, 4,6-quinolinyl, 4,7-quinolinyl, 4,8-quinolinyl,1,4-isoquinolinyl, 1,5-isoquinolinyl, 1,6-isoquinolinyl,1,7-isoquinolinyl, 1,8-isoquinolinyl, 3,4-isoquinolinyl,3,5-isoquinolinyl, 3,6-isoquinolinyl, 3,7-isoquinolinyl,3,8-isoquinolinyl, 4,5-isoquinolinyl, 4,6-isoquinolinyl,4,7-isoquinolinyl, 4,8-isoquinolinyl, 3,4-cinnolinyl, 3,5-cinnolinyl,3,6-cinnolinyl, 3,7-cinnolinyl, 3,8-cinnolinyl, 4,5-cinnolinyl,4,6-cinnolinyl, 4,7-cinnolinyl, and 4,8-cinnolinyl, and each carbon andhydrido containing nitrogen member of the ring of the W⁶ other than thepoints of attachment is optionally substituted with one or more of thegroup consisting of R⁹, R^(10, R) ¹¹, and R¹², with the proviso thatQ^(b) is bonded to highest number substituent position of each W⁶ andthat (CH(R³⁸))_(r) is bonded to E⁰.

In an embodiment of compounds of Formula I or a pharmaceuticallyacceptable salt thereof,

J is selected from the group consisting of O and S;

J is optionally selected from the group consisting of CH—R⁶ and N—R⁶wherein R⁶ is a linear spacer moiety having a chain length of 1 to 4atoms linked to the point of bonding of a substituent selected from thegroup consisting of R^(4a), R^(4b), R³⁹, R⁴⁰, R⁵, R¹⁴, and R¹⁵ to form aheterocyclyl ring having 5 through 8 contiguous members;

B is formula (V):

 wherein D¹, D², J¹, J² and K¹ are independently selected from the groupconsisting of C, N, O, S and a covalent bond with the provisos that nomore than one is a covalent bond, no more than one of D¹, D², J¹, J² andK¹ is O, no more than one of D¹, D², J¹, J² and K² is S, one of D¹, D²,J¹, J² and K¹ must be a covalent bond when two of D¹, D², and J¹, J² andK¹ are O and S, and no more than four of D¹, D², J¹, J² and K¹ are Nwith the proviso that R³², R³³, R³⁴, R³⁵, and R³⁶ are each independentlyselected to maintain the tetravalent nature of carbon, trivalent natureof nitrogen, the divalent nature of sulfur, and the divalent nature ofoxygen;

R⁹, R¹⁰, R^(11, R) ¹², R¹³, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R³², R³³, R³⁴, R³⁵, andR³⁶ are independently selected from the group consisting of hydrido,acetamido, haloacetamido, amidino, guanidino, dialkylsulfonium,trialkylphosphonium, dialkylsulfoniumalkyl, carboxy, heteroaralkylthio,heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aryloylalkoxy,heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl,heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl,aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl,cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl,cycloalkylsulfonylalkyl, heteroarylamino,N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, haloalkylthio,alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy,cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy,cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl,hydroxy, amino, alkoxyamino, thio, nitro, lower alkylamino, alkylthio,alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl,heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl,arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl,heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl,haloalkylsutfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido,alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkylamidosulfonyl, monoarylamidosulfonyl, arylsulfonamido,diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl,arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl,heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl,heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl,alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy,cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl,lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy,hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, alkylenylamino,hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy,aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl,heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl,heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl,carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido,arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboxy,carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy,phosphono, phosphonoalkyl, diaralkoxyphosphono, anddiaralkoxyphosphonoalkyl;

R¹⁶, R¹⁹, R³², R³³, R³⁴, R³⁵, and R³⁶ are independently optionally Q^(b)with the proviso that no more than one of R¹⁶ and R¹⁹ is Q^(b) at thesame time and that Q^(b) is Q^(be);

R³² and R³³, R³³ and R³⁴, R³⁴ and R³⁵, and R³⁵ and R³⁶ are independentlyoptionally selected to form a spacer pair wherein a spacer pair is takentogether to form a linear moiety having from 3 through 6 contiguousatoms connecting the points of bonding of said spacer pair members toform a ring selected from the group consisting of a cycloalkenyl ringhaving 5 through 8 contiguous members, a partially saturatedheterocyclyl ring having 5 through 8 contiguous members, a heteroarylring having 5 through 6 contiguous members, and an aryl with the provisothat no more than one of the group consisting of spacer pairs R³² andR³³, R³³ and R³⁴, R³⁴ and R³⁵, and R³⁵ and R³⁶ can be used at the sametime;

R⁹ and R¹⁰, R¹⁰ and R¹¹, R¹¹ and R¹², and R¹² and R¹³ are independentlyoptionally selected to form a spacer pair wherein a spacer pair is takentogether to form a linear moiety having from 3 through 6 contiguousatoms connecting the points of bonding of said spacer pair members toform a ring selected from the group consisting of a cycloalkenyl ringhaving 5 through 8 contiguous members, a partially saturatedheterocyclyl ring having 5 through 8 contiguous members, a heteroarylring having 5 through 6 contiguous members, and an aryl with the provisothat no more than one of the group consisting of spacer pairs R⁹ andR¹⁰, R¹⁰ and R¹¹, R¹¹ and R¹², and R¹² and R¹³ can be used at the sametime;

B is optionally selected from the group consisting of hydrido,trialkylsilyl, C2-C8 alky, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8alkynyl, C2-C8 haloalkyl, and C3-C8 haloalkenyl wherein each member ofgroup B may be optionally substituted at any carbon up to and including6 atoms from the point of attachment of B to A with one or more of thegroup consisting of R³², R³³, R³⁴, R³⁵, and R³⁶;

B is optionally selected from the group consisting of C3-C15 cycloalkyl,C5-C10 cycloalkenyl, C4-C12 saturated heterocyclyl, and C4-C9 partiallysaturated heterocyclyl, wherein each ring carbon is optionallysubstituted with R³³, a ring carbon other than the ring carbon at thepoint of attachment of B to A is optionally substituted with oxoprovided that no more than one ring carbon is substituted by oxo at thesame time, ring carbon and nitrogen atoms adjacent to the carbon atom atthe point of attachment is optionally substituted with R⁹ or R¹³, a ringcarbon or nitrogen atom adjacent to the R⁹ position and two atoms fromthe point of attachment is optionally substituted with R¹⁰, a ringcarbon or nitrogen atom adjacent to the R¹³ position and two atoms fromthe point of attachment is optionally substituted with R¹², a ringcarbon or nitrogen atom three atoms from the point of attachment andadjacent to the R¹⁰ position is optionally substituted with R¹¹ a ringcarbon or nitrogen atom three atoms from the point of attachment andadjacent to the R¹² position is optionally substituted with R³³, and aring carbon or nitrogen atom four atoms from the point of attachment andadjacent to the R¹¹ and R³³ positions is optionally substituted withR^(34;)

A is selected from the group consisting of single covalent bond,(W⁷)_(rr)—(CH(R¹⁵))_(pa) and (CH(R¹⁵))_(pa)—(W⁷)_(rr) wherein rr is aninteger selected from 0 through 1, pa is an integer selected from 0through 6, and W⁷ is selected from the group consisting of O, S, C(O),C(S), C(O)S, C(S)O, C(O)N(R⁷), C(S)N(R⁷), (R⁷)NC(O), (R⁷)NC(S), S(O),S(O)₂, S(O)₂N(R⁷), (R⁷)NS(O)₂, P(O)(R⁸), N(R⁷)P(O)(R⁸), P(O)(R⁸)N(R⁷),C(NR⁷)N(R⁷), (R⁷)NC(NR⁷), (R⁷)NC(NR⁷)NR⁷, and N(R⁷) with the provisothat no more than one of the group consisting of rr and pa can be 0 atthe same time;

R⁷ and R⁸ are independently selected from the group consisting ofhydrido, hydroxy, alkyl, acyl, aroyl, heteroaroyl, and alkoxyalkyl;

R¹⁴, R¹⁵, R³⁷, and R³⁸ are independently selected from the groupconsisting of hydrido, hydroxy, halo, cyano, hydroxyalkyl, alkoxy,alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,cycloalkenylalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl,haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl,halocycloalkenyloxyalkyl, carboxy, carboxyalkyl, carboalkoxy,carboxamide, and carboxamidoalkyl;

R¹⁴ and R³⁸ can be independently selected from the group consisting ofacyl, aroyl, and heteroaroyl with the proviso that acyl is selected fromother than formyl and 2-oxoacyl;

Ψ is selected from the group consisting of NR⁵, O, C(O), C(S), S, S(O),S(O)₂, ON(R⁵), P(O)(R⁸), and CR³⁹R⁴⁰;

R⁵ is selected from the group consisting of hydrido, hydroxy, amino,alkyl, alkoxy, alkoxyalkyl, haloalkyl, acyl, aroyl, and heteroaroyl;

R³⁹ and R⁴⁰ are independently selected from the group consisting ofhydrido, hydroxy, halo, cyano, hydroxyalkyl, acyl, aroyl, heteroaroyl,acylamido, alkoxy, alkyl, alkoxyalkyl, haloalkyl, haloalkoxy,haloalkoxyalkyl, alkylsulfonyl, haloalkylsulfonyl, carboxy,carboxyalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;

M is selected from the group consisting of N and R¹—C;

R² and R¹ are independently selected from the group consisting of Z⁰—Q,hydrido, alkyl, alkenyl, and halo;

R¹ is optionally selected from the group consisting of amino,aminoalkyl, alkylamino, amidino, guanidino, hydroxy, hydroxyamino,alkoxy, hydroxyalkyl, alkoxyamino, thiol, alkylthio, dialkylsulfonium,trialkylphosphonium, dialkylsulfoniumalkyl, heteroarylamino, nitro,arylamino, aralkylamino, alkanoyl, alkenoyl, aroyl, heteroaroyl,aralkanoyl, heteroaralkanoyl, haloalkanoyl, hydroxyhaloalkyl, cyano, andphosphono;

Z⁰ is selected from the group consisting of covalent single bond,(CR⁴¹R⁴²)_(q) wherein q is an integer selected from 1 through 6,(CH(R⁴¹))_(g)—W⁰—(CH(R⁴²))_(p) wherein g and p are integersindependently selected from 0 through 3 and W⁰ is selected from thegroup consisting of O, S, C(O), C(S), C(O)O, C(S)O, C(O)S, C(S)S,C(O)N(R⁴¹), (R⁴¹)NC(O), C(S)N(R⁴¹), (R⁴¹)NC(S), OC(O)N(R⁴¹),(R⁴¹)NC(O)O, SC(S)N(R⁴¹), (R⁴¹)NC(S)S, SC(O)N(R⁴¹), (R⁴¹)NC(O)S,OC(S)N(R⁴¹), (R⁴¹)NC(S)O, N(R⁴²)C(O)N(R), (R⁴¹)NC(O)N(R⁴²,N(R⁴²)C(S)N(R⁴¹), (R⁴¹)NC(S)N(R⁴²), S(O), S(O)₂, S(O)₂N(R⁴¹),N(R⁴¹)S(O)₂, Se, Se(O), Se(O)₂, Se(O)₂N(R⁴¹), N(R⁴¹)Se(O)₂, P(O)(R⁸),N(R⁷)P(O)(R⁸), P(O)(R⁸)N(R⁷), N(R⁴¹), ON(R⁴¹), and SiR²⁸R²⁹, and(CH(R⁴¹))_(e)—W²²—(CH(R⁴²))_(h) wherein e and h are integersindependently selected from 0 through 2 and W²² is selected from thegroup consisting of CR⁴¹═CR⁴², CR⁴¹R⁴²═C; vinylidene), ethynylidene(C≡C; 1,2-ethynyl), 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl,1,3-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl,2,4-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl,1,2-piperazinyl, 1,3-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl,1,2-piperidinyl, 1,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl,2,6-piperidinyl, 3,4-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl,2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl,2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, and3,4-tetrahydrofuranyl, with the provisos that R⁴¹ and R⁴² are selectedfrom other than halo and cyano when directly bonded to N and Z⁰ isdirectly bonded to the pyrimidinone ring;

R⁴¹ and R⁴² are independently selected from the group consisting ofamidino, hydroxyamino, hydrido, hydroxy, amino, halo, cyano, aryloxy,hydroxyalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, alkoxy,alkyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkylalkoxy, alkoxyalkyl,heteroaryloxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl,cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl,halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl,saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl,heteroaralkyl, heteroarylthioalkyl, heteroaralkylthioalkyl,alkylsulfonyl, haloalkylsulfonyl, arylsulfonyl, arylsulfonylalkyl,aralkylsulfonyl, cycloalkylsulfonyl, cycloalkylsufonylalkyl,heteroarylsulfonylalkyl, heteroarylsulfonyl, and aralkylsulfonylalkyl;

Q is formula (II):

 wherein D¹, D², J¹, J² and K¹ are independently selected from the groupconsisting of C, N, O, S and a covalent bond with the provisos that nomore than one is a covalent bond, no more than one of D¹, D², J¹, J² andK¹ is O, no more than one of D¹, D², J¹, J² and K¹ is S, one of D¹, D²,J¹, J² and K¹ must be a covalent bond when two of D¹, D², J¹, J² and K¹are O and S, and no more than four of D¹, D², J¹, J² and K¹ are N, withthe proviso that R⁹, R¹⁰, R¹¹, R¹², and R¹³ are each independentlyselected to maintain the tetravalent nature of carbon, trivalent natureof nitrogen, the divalent nature of sulfur, and the divalent nature ofoxygen;

Q is optionally selected from formula (III):

 wherein D³, D⁴, J³, and J⁴ are independently selected from the groupconsisting of C, N, O, and S, no more than one of D³, D⁴, J³, and J⁴ isO, no more than one of D³, D⁴, J³, and J⁴ is S, and no more than threeof D¹, D², J¹, and J² are N with the proviso that R⁹, R¹⁰, R¹¹, and R¹²are each independently selected to maintain the tetravalent nature ofcarbon, trivalent nature of nitrogen, the divalent nature of sulfur, andthe divalent nature of oxygen;

Q is optionally selected from the group consisting of hydrido, alkyl,alkoxy, alkylamino, alkylthio, haloalkylthio, alkenyl, alkynyl,saturated heterocyclyl, partially saturated heterocyclyl, acyl, aroyl,heteroaroyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,cycloalkenylalkyl, cycloalkylalkenyl, haloalkyl, haloalkoxy,haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl,haloalkenyloxyalkyl, halocycloalkoxyalkyl, and halocycloalkenyloxyalkylwith the proviso that Z⁰ is selected from other than a single covalentbond when Q is hydrido;

K is (CR^(4a)R^(4b))_(n) wherein n is an integer selected from 1 through2;

R^(4a) and R^(4b) are independently selected from the group consistingof halo, hydrido, hydroxy, cyano, hydroxyalkyl, alkyl, alkenyl,alkoxyalkyl, aralkyl, heteroaralkyl, alkylthioalkyl, haloalkyl,haloalkenyl, and cyanoalkyl;

E⁰ is E¹, when K is (CR^(4a)R^(4b))_(n), wherein E¹ is selected from thegroup consisting of a covalent single bond, O, S, C(O), C(S), C(O)O,C(S)O, C(O)S, C(S)S, C(O)N(R⁷), (R⁷)NC(O), C(S)N(R⁷), (R⁷)NC(S),OC(O)N(R⁷), (R⁷)NC(O)O, SC(S)N(R⁷), (R⁷)NC(S)S, SC(O)N(R⁷), (R⁷)NC(O)S,OC(S)N(R⁷), (R⁷)NC(S)O, N(R⁸)C(O)N(R⁷), (R⁷)NC(O)N(R⁸), N(R⁸)C(S)N(R⁷),(R⁷)NC(S)N(R⁸), S(O), S(O)₂, S(O)₂N(R⁷), N(R⁷)S(O)₂, S(O)₂N(R⁷)C(O),C(O)N(R⁷)S(O)₂, P(O)(R⁸), N(R⁷)P(O)(R⁸), P(O)(R⁸)N(R⁷), N(R⁷), ON(R⁷),CR^(4a)═CR^(4b), ethynylidene (C≡C; 1,2-ethynyl), and C═CR^(4a)R^(4b);

K is optionally (CH(R¹⁴))_(j)—T wherein j is selected from a integerfrom 0 through 2 and T is selected from the group consisting of singlecovalent bond, O, S, and N(R⁷) with the proviso that (CH(R¹⁴))_(j) isbonded to the pyrimidinone ring;

E⁰ is optionally E², when K is (CH(R¹⁴))_(j)—T, wherein E² is selectedfrom the group consisting of a covalent single bond, C(O), C(S), C(O)O,C(S)O, C(O)S, C(S)S, C(O)N(R⁷), (R⁷)NC(O), C(S)N(R⁷), (R⁷)NC(S),(R⁷)NC(O)O, (R⁷)NC(S)S, (R⁷)NC(O)S, (R⁷)NC(S)O, N(R⁸)C(O)N(R⁷),(R⁷)NC(O)N(R⁸), N(R⁸)C(S)N(R⁷), (R⁷)NC(S)N(R⁸), S(O), S(O)₂, S(O)₂N(R⁷),N(R⁷)S(O)₂, S(O)₂N(H)C(O), C(O)N(H)S(O)₂, P(O)(R⁸), N(R⁷)P(O)(R⁸),P(O)(R⁸)N(R⁷), and N(R⁷);

K is optionally G—(CH(R¹⁵))_(k) wherein k is selected from an integerfrom 1 through 2 and G is selected from the group consisting of O, S,and N(R⁷) with the proviso that R¹⁵ is other than hydroxy, cyano, halo,amino, alkylamino, dialkylamino, and sulfhydryl when k is 1;

E⁰ is optionally E³ when K is G—(CH(R¹⁵))_(k), wherein E³ is selectedfrom the group consisting of a covalent single bond, O, S, C(O), C(S),C(O)O, C(S)O, C(O)S, C(S)S, C(O)N(R⁷), (R⁷)NC(O), C(S)N(R⁷), (R⁷)NC(S),OC(O)N(R⁷), (R⁷)NC(O)O, SC(S)N(R⁷),(R⁷)NC(S)S, SC(O)N(R⁷), (R⁷)NC(O)S,OC(S)N(R⁷), (R⁷)NC(S)O, N(R⁸)C(O)N(R⁷), (R⁷)NC(O)N(R⁸), N(R⁸)C(S)N(R⁷),(R⁷)NC(S)N(R⁸), S(O), S(O)₂, S(O)₂N(R⁷), N(R⁷)S(O)₂, P(O)(R⁸),N(R⁷)P(O)(R⁸), P(O)(R⁸)N(R⁷), N(R⁷), ON(R⁷), CR^(4a)═CR^(4b),ethynylidene (C≡C; 1,2-ethynyl), and C═CR^(4a)R^(4b);

Y⁰ is formula (IV):

 wherein D⁵, D⁶, J⁵, and J⁶ are independently selected from the groupconsisting of C, N, O, S and a covalent bond with the provisos that nomore than one is a covalent bond, K² is independently selected from thegroup consisting of C and N⁺, no more than one of D⁵, D⁵, J⁵, and J⁶ isO, no more than one of D⁵, D⁶, J⁵, and J⁶ is one of D⁵, D⁶, J⁵, and J⁶must be a covalent bond when two of D⁵, D⁶, J⁵, and J⁶ are O and S, nomore than three of D⁵, D⁶, J⁵, and J⁶ is N when K² is N⁺, and no morethan four of D⁵, D⁶, J⁵, and J⁶ are N when K² is carbon with theprovisos that R¹⁶, R¹⁷, R¹⁸, and R¹⁹ are each independently selected tomaintain the tetravalent nature of carbon, trivalent nature of nitrogen,the divalent nature of sulfur, and the divalent nature of oxygen;

R¹⁶ and R¹⁷ are optionally independently taken together to form a linearmoiety spacer having from 3 through 6 contiguous atoms connected to forma ring selected from the group consisting of a cycloalkenyl ring havingfrom 5 through 8 contiguous members, a partially saturated heterocyclylring having from 5 through 8 contiguous members, a heteroaryl havingfrom 5 through 6 contiguous members, and an aryl;

Q^(b) is selected from the group consisting of NR²⁰R²¹, ⁺NR²⁰R²¹R²²,oxy, alkyl, aminoalkylenyl, alkylamino, dialkylamino,dialkylsulfoniumalkyl, acylamino and Q^(be) , wherein Q^(be) is hydridoand R²⁰, R²¹, and R²² are independently selected from the groupconsisting of hydrido, amino, alkyl, hydroxy, alkoxy,aminoalkylenyl,alkylamino, dialkylamino, and hydroxyalkyl with theprovisos that no more than one of R²⁰, R²¹, and R²² is hydroxy, alkoxy,alkylamino, amino, and dialkylamino at the same time and that R²⁰, R²¹,and R²² must be other than be hydroxy, alkoxy, alkylamino, amino, anddialkylamino when K² is N⁺;

R²⁰ and R²¹, R²⁰ and R²², and R²¹ and R²² are independently optionallyselected to form a spacer pair wherein a spacer pair is taken togetherto form a linear moiety having from 4 through 7 contiguous atomsconnecting the points of bonding of said spacer pair members to form aheterocyclyl ring having 5 through 8 contiguous members with the provisothat no more than one of the group consisting of spacer pairs R²⁰ andR²¹, R²⁰ and R²², and R²¹ and R²² is used at the same time;

Q^(b) is optionally selected from the group consisting ofN(R²⁶)SO₂N(R²³)(R²⁴), N(R²⁶)C(O)OR⁵, N(R²⁶)C(O)SR⁵, N(R²⁶)C(S)OR⁵ andN(R²⁶)C(S)SR⁵ with the proviso that no more than one of R²³, R²⁴, andR²⁶ is hydroxy, alkoxy, alkylamino, amino, and dialkylamino when two ofthe group consisting of R²³, R²⁴, and R²⁶ are bonded to the same atom;

Q^(b) is optionally selected from the group consisting ofdialkylsulfonium, trialkylphosphonium, C(NR²⁵)NR²³R²⁴,N(R²⁶)C(NR²⁵)N(R²³)(R²⁴), N(R²⁶)C(O)N(R²³)(R²⁴), N(R²⁶)C(S)N(R²³)(R²⁴),C(NR²⁵)OR⁵, C(O)N(R²⁶)C(NR²⁵)N(R²³)(R²⁴), C(S)N(R²⁶)C(NR²⁵)N(R²³)(R²⁴),N(R²⁶)N(R²⁶)C(NR²⁵)N(R²³)(R²⁴), ON(R²⁶)C(NR²⁵N(R²³)(R^(24), N(R)²⁶)N(R²⁶)SO₂N(R²³)(R²⁴), C(NR²⁵)SR⁵, C(O)NR²³R²⁴, and C(O)NR²³R²⁴ withthe provisos that no more than one of R²³, R²⁴, and R²⁶ can be hydroxy,alkoxy, alkylaminol, amino, or dialkylamino when two of the groupconsisting of R²³, R²⁴, and R²⁶ are bonded to the same atom and thatsaid Q^(b) group is bonded directly to a carbon atom;

R²³, R²⁴, R²⁵, and R²⁶ are independently selected from the groupconsisting of hydrido, alkyl, hydroxy, alkoxy, aminoalkylenyl,alkylamino, dialkylamino, amino, and hydroxyalkyl;

R²³ and R²⁴ are optionally taken together to form a linear spacer moietyhaving from 4 through 7 contiguous atoms connecting the points ofbonding to form a heterocyclyl ring having 5 through 8 contiguousmembers;

Q^(s) is selected from the group consisting of a single covalent bond,(CR³⁷R³⁸)_(b)—(W⁰)_(az) wherein az is an integer selected from 0 through1, b is an integer selected from 1 through 4, and W⁰ is selected fromthe group consisting of O, S, C(O), C(S), C(O)O, C(S)O, C(O)S, C(S)S,C(O)N(R¹⁴), (R¹⁴)NC(O), C(S)N(R¹⁴), (R¹⁴)NC(S), OC(O)N(R¹⁴),SC(S)N(R¹⁴), SC(O)N(R¹⁴), OC(S)N(R¹⁴), N(R¹⁵)C(O)N(R¹⁴),(R¹⁴)NC(O)N(R¹⁵), N(R¹⁵)C(S)N(R¹⁴), (R¹⁴)NC(S)N(R¹⁵), S(O), S(O)₂,S(O)₂N(R¹⁴), N(R¹⁴)S(O)₂, P(O)(R⁸), N(R⁷)P(O)(R⁸), P(O)(R⁸)N(R⁷),N(R¹⁴), ON(R¹⁴), (CH(R¹⁴))_(c)—W¹—(CH(R¹⁵))_(d) wherein c and d areintegers independently selected from 1 through 4, and W¹ is selectedfrom the group consisting of O, S, C(O), C(S), C(O)O, C(S)O, C(O)S,C(S)S, C(O)N(R¹⁴), (R¹⁴)NC(O), C(S)N(R¹⁴), (R¹⁴)NC(S), OC(O)N(R¹⁴),(R¹⁴)NC(O)O, SC(S)N(R¹⁴), (R¹⁴)NC(S)S, SC(O)N(R¹⁴), (R¹⁴)NC(O)S,OC(S)N(R¹⁴), (R¹⁴)NC(S)O, N(R¹⁵)C(O)N(R¹⁴), (R¹⁴)NC(O)N(R¹⁵),N(R¹⁵)C(S)N(R¹⁴), (R¹⁴)NC(S)N(R¹⁵), S(O), S(O)₂, S(O)₂N(R¹⁴),N(R¹⁴)S(O)², P(O)(R⁸), N(R⁷)P(O)(R⁸), P(O)(R⁸)N(R⁷), N(R¹⁴), ON(R¹⁴),and (CH(R¹⁴))_(e)—W²²—(CH(R¹⁵))_(h) wherein e and h are integersindependently selected from 0 through 2 and W²² is selected from thegroup consisting of CR⁴¹═CR⁴², CR⁴¹R⁴²═C; vinylidene), ethynylidene(C≡C; 1,2-ethynyl), 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl,1,3-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl,2,4-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl,1,2-piperazinyl, 1,3-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl,1,2-piperidinyl, 1,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl,2,6-piperidinyl, 3,4-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl,2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl,2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, and3,4-tetrahydrofuranyl, with the provisos that R¹⁴ and R¹⁵ are selectedfrom other than halo and cyano when directly bonded to N and that(CR³⁷R³⁸)_(b), (CH(R¹⁴))_(c), (CH(R¹⁴))_(e) and are bonded to E⁰;

Y⁰ is optionally Q^(b)—Q^(ss) wherein Q^(ss) is selected from the groupconsisting of (CR³⁷R³⁸)_(f) wherein f is an integer selected from 1through 6, (CH(R¹⁴))_(c)—W¹—(CH(R¹⁵))_(d) wherein c and d are integersindependently selected from 1 through 4, and W¹ is selected from thegroup consisting of W¹ is selected from the group consisting of O, S,C(O), C(S), C(O)O, C(S)O, C(O)S, C(S)S, C(O)N(R¹⁴), (R¹⁴)NC(O),C(S)N(R¹⁴), (R¹⁴)NC(S), OC(O)N(R¹⁴), (R¹⁴)NC(O)O, SC(S)N(R¹⁴),(R¹⁴)NC(S)S, SC(O)N(R¹⁴), (R¹⁴)NC(O)S, OC(S)N(R¹⁴), (R¹⁴)NC(S),N(R¹⁵)C(O)N(R¹⁴), (R¹⁴)NC(O)N(R¹⁵), N(R¹⁵)C(S)N(R¹⁴), (R¹⁴)NC(S)N(R¹⁵),S(O), S(O)₂, S(O)₂N(R¹⁴), N(R¹⁴)S(O)₂, P(O)(R⁸), N(R⁷)P(O)(R⁸),P(O)(R⁸)N(R⁷), N(R¹⁴), ON(R¹⁴), and (CH(R¹⁴))_(e)—W²—(CH(R¹⁵))_(h)wherein e and h are integers independently selected from 0 through 2 andW² is selected from the group consisting of CR^(4a)═CR^(4b),ethynylidene (C≡C; 1,2-ethynyl), and C═CR^(4a)R^(4b) with the provisosthat R¹⁴ and R¹⁵ are selected from other than halo and cyano whendirectly bonded to N and that (CR³⁷ R³⁸)_(f), (CH(R¹⁴))_(c), and(CH(R¹⁴))_(e) are bonded to E⁰;

Y⁰ is optiionally Q^(b)—Q^(sss) wherein Q^(sss) is (CH(R³⁸))_(r)—W³, ris an integer selected from 1 through 3, W³ is selected from the groupconsisting of 1,1-cyclopropyl, 1,2-cyclopropyl, 1,1-cyclobutyl,1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl,1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl,2,5-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl,1,2-piperazinyl, 1,3-piperazinyl, 1,4-piperazinyl, 2,3-piperazinyl,2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl,1,4-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,5-piperidinyl,2,6-piperidinyl, 3,4-piperidinyl, 3,5-piperidinyl, 3,6-piperidinyl,1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl,2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2H-2,3-pyranyl, 2H-2,4-pyranyl,2H-2,5-pyranyl, 4H-2,3-pyranyl, 4H-2,4-pyranyl, 4H-2,5-pyranyl,2H-pyran-2-one-3,4-yl, 2H-pyran-2-one-4,5-yl, 4H-pyran-4-one-2,3-yl,2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl,3,4-tetrahydrofuranyl, 2,3-tetrahydropyranyl, 2,4-tetrahydropyranyl,2,5-tetrahydropyranyl, 2,6-tetrahydropyranyl, 3,4-tetrahydropyranyl, and3,5-tetrahydropyranyl, and each carbon and hyrido containing nitrogenmember of the ring of the W³ other than the points of attachment isoptionally substituted with one or more of the group consisting of R⁹,R¹⁰, R¹¹, and R¹², with the proviso that (CH(R³⁸))_(r) is bonded to E⁰and Q^(b) is bonded to lowest numbered substituent position of each W³;

Y⁰ is optionally Q^(b)—Q^(sssr) wherein Q^(sssr) is (CH(R³⁸))_(r)—W⁴, ris an integer selected from 1 through 3, W⁴ is selected from the groupconsisting of 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl,1,4-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl,2,4-morpholinyl, 2,5-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl,3,5-morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 1,4-piperazinyl,2,3-piperazinyl, 2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl,1,3-piperidinyl, 1,4-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl,2,5-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 3,5-piperidinyl,3,6-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl,2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2H-2,3-pyranyl,2H-2,4-pyranyl, 2H-2,5-pyranyl, 4H-2,3-pyranyl, 4H-2,4-pyranyl,4H-2,5-pyranyl, 2H-pyran-2-one-3,4-yl, 2H-pyran-2-one-4,5-yl,4H-pyran-4-one-2,3-yl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl,2,5-tetrahydrofuranyl, 3,4-tetrahydrofuranyl, 2,3-tetrahydropyranyl,2,4-tetrahydropyranyl, 2,5-tetrahydropyranyl, 2,6-tetrahydropyranyl,3,4-tetrahydropyranyl, and 3,5-tetrahydropyranyl, and each carbon andhydrido containing nitrogen member of the ring of the W⁴ other than thepoints of attachment is optionally substituted with one or more of thegroup consisting of R⁹, R¹⁰, R¹¹, and R¹², with the provisos that(CH(R³⁸))_(r) is bonded to E⁰ and Q^(b) is bonded to highest numbersubstituent position of each W⁴;

Y⁰ is optionally Q^(b)—Q^(ssss) wherein Q^(ssss) is (CH(R³⁸))_(r)—W⁵, ris an integer selected from 1 through 3, W⁵ is selected from the groupconsisting of 1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7-indenyl,2,7-indenyl, 2,6-indenyl, 2,5-indenyl, 2,4-indenyl, 3,4-indenyl,3,5-indenyl, 3,6-indenyl, 3,7-indenyl, 2,4-benzofuranyl,2,5-benzofuranyl, 2,6-benzofuranyl, 2,7-benzofuranyl, 3,4-benzofuranyl,3,5-benzofuranyl, 3,6-benzofuranyl, 3,7-benzofuranyl,2,4-benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl,2,7-benzothiophenyl, 3,4-benzothiophenyl, 3,5-benzothiophenyl,3,6-benzothiophenyl, 3,7-benzothiophenyl, 2,7-imidazo(1,2-a)pyridinyl,3,4-imidazo(1,2-a)pyridinyl, 3,5-imidazo(1,2-a)pyridinyl,3,6-imidazo(1,2-a)pyridinyl, 3,7-imidazo(1,2-a)pyridinyl, 2,4-indolyl,2,5-indolyl, 2,6-indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl,3,6-indolyl, 3,7-indolyl, 1,4-isoindolyl, 1,5-isoindolyl,1,6-isoindolyl, 2,4-isoindolyl, 2,5-isoindolyl, 2,6-isoindolyl,2,7-isoindolyl, 1,3-isoindolyl, 3,4-indazolyl, 3,5-indazolyl,3,6-indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl, 2,5-benzoxazolyl,2,6-benzoxazolyl, 2,7-benzoxazolyl, 3,4-benzisoxazolyl,3,5-benzisoxazolyl, 3,6-benzisoxazolyl, 3,7-benzisoxazolyl,1,4-naphthyl, 1,5-naphthyl, 1,6-naphthyl, 1,7-naphthyl, 1,8-naphthyl,2,4-naphthyl, 2,5-naphthyl, 2,6-naphthyl, 2,7-naphthyl, 2,8-naphthyl,2,4-quinolinyl, 2,5-quinolinyl, 2,6-quinolinyl, 2,7-quinolinyl,2,8-quinolinyl, 3,4-quinolinyl, 3,5-quinolinyl, 3,6-quinolinyl,3,7-quinolinyl, 3,8-quinolinyl, 4,5-quinolinyl, 4,6-quinolinyl,4,7-quinolinyl, 4,8-quinolinyl, 1,4-isoquinolinyl, 1,5-isoquinolinyl,1,6-isoquinolinyl, 1,7-isoquinolinyl, 1,8-isoquinolinyl,3,4-isoquinolinyl, 3,5-isoquinolinyl, 3,6-isoquinolinyl,3,7-isoquinolinyl, 3,8-isoquinolinyl, 4,5-isoquinolinyl,4,6-isoquinolinyl, 4,7-isoquinolinyl, 4,8-isoquinolinyl, 3,4-cinnolinyl,3,5-cinnolinyl, 3,6-cinnolinyl, 3,7-cinnolinyl, 3,8-cinnolinyl,4,5-cinnolinyl, 4,6-cinnolinyl, 4,7-cinnolinyl, and 4,8-cinnolinyl, andeach carbon and hydrido containing nitrogen member of the ring of the W⁵other than the points of attachment is optionally substituted with oneor more of the group consisting of R⁹, R¹⁰, R¹¹, and R¹², with theproviso that (Q^(b) is bonded to lowest number substituent position ofeach W⁵ and that (CH(R³⁸))_(r) is bonded to E⁰;

Y⁰ is optionally Q^(b)—Q^(ssssr) wherein Q^(ssssr) is (CH(R³⁸))_(r)—W⁶,r is an integer selected from 1 through 3, W⁶ is selected from the groupconsisting of 1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7-indenyl,2,7-indenyl, 2,6-indenyl, 2,5-indenyl, 2,4-indenyl, 3,4-indenyl,3,5-indenyl, 3,6-indenyl, 3,7-indenyl, 2,4-benzofuranyl,2,5-benzofuranyl, 2,6-benzofuranyl, 2,7-benzofuranyl, 3,4-benzofuranyl,3,5-benzofuranyl, 3,6-benzofuranyl, 3,7-benzofuranyl,2,4-benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl,2,7-benzothiophenyl, 3,4-benzothiophenyl, 3,5-benzothiophenyl,3,6-benzothiophenyl, 3,7-benzothiophenyl, 2,7-imidazo(1,2-a)pyridinyl,3,4-imidazo(1,2-a)pyridinyl, 3,5-imidazo(1,2-a)pyridinyl,3,6-imidazo(1,2-a)pyridinyl, 3,7-imidazo(1,2-a)pyridinyl, 2,4-indolyl,2,5-indolyl, 2,6-indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl,3,6-indolyl, 3,7-indolyl, 1,4-isoindolyl, 1,5-isoindolyl,1,6-isoindolyl, 2,4-isoindolyl, 2,5-isoindolyl, 2,6-isoindolyl,2,7-isoindolyl, 1,3-isoindolyl, 3,4-indazolyl, 3,5-indazolyl,3,6-indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl, 2,5-benzoxazolyl,2,6-benzoxazolyl, 2,7-benzoxazolyl, 3,4-benzisoxazolyl,3,5-benzisoxazolyl, 3,6-benzisoxazolyl, 3,7-benzisoxazolyl,1,4-naphthyl, 1,5-naphthyl, 1,6-naphthyl, 1,7-naphthyl, 1,8-naphthyl,2,4-naphthyl, 2,5-naphthyl, 2,6-naphthyl, 2,7-naphthyl, 2,8-naphthyl,2,4-quinolinyl, 2,5-quinolinyl, 2,6-quinolinyl, 2,7-quinolinyl,2,8-quinolinyl, 3,4-quinolinyl, 3,5-quinolinyl, 3,6-quinolinyl,3,7-quinolinyl, 3,8-quinolinyl, 4,5-quinolinyl, 4,6-quinolinyl,4,7-quinolinyl, 4,8-quinolinyl, 1,4-isoquinolinyl, 1,5-isoquinolinyl,1,6-isoquinolinyl, 1,7-isoquinolinyl, 1,8-isoquinolinyl,3,4-isoquinolinyl, 3,5-isoquinolinyl, 3,6-isoquinolinyl,3,7-isoquinolinyl, 3,8-isoquinolinyl, 4,5-isoquinolinyl,4,6-isoquinolinyl, 4,7-isoquinolinyl, 4,8-isoquinolinyl, 3,4-cinnolinyl,3,5-cinnolinyl, 3,6-cinnolinyl, 3,7-cinnolinyl, 3,8-cinnolinyl,4,5-cinnolinyl, 4,6-cinnolinyl, 4,7-cinnolinyl, and 4,8-cinnolinyl, andeach carbon and hydrido containing nitrogen member of the ring of the W⁶other than the points of attachment is optionally substituted with oneor more of the group consisting of R⁹, R¹⁰, R¹¹, and R¹², with theproviso that Q^(b) is bonded to highest number substituent position ofeach W⁶ and that (CH(R³⁸))_(r) is bonded to E⁰.

In another embodiment of compounds of Formula I or a pharmaceuticallyacceptable salt thereof,

J is selected from the group consisting of O and S;

B is formula (V):

 wherein D¹, D², J¹, J² and K¹ are independently selected from the groupconsisting of C, N, O, S and a covalent bond with the provisos that nomore than one is a covalent bond, no more than one of D¹, D², J¹, J² andK¹ is O, no more than one of D¹, D², J¹, J² and K¹ is S, one of D¹, D²,J¹, J² and K¹ must be a covalent bond when two of D¹, D², J¹, J² and K¹are O and S, and no more than four of D¹, D², J¹, J² and K¹ are N;

R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R³², R³³, R³⁴, R³⁵, and R³⁶are independently selected from the group consisting of hydrido,acetamido, haloacetamido, amidino, guanidino, dialkylsulfonium,trialkylphosphonium, dialkylsulfoniumalkyl, carboxy, heteroaralkylthio,heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aryloylalkoxy,heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl,heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl,aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl,cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl,cycloalkylsulfonylalkyl, heteroarylamino,N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, haloalkylthio,alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy,cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy,cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl,hydroxy, amino, alkoxyamino, thio, nitro, lower alkylamino, alkylthio,alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl,heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl,arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl,heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl,haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido,alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkylamidosulfonyl, monoarylamidosulfonyl, arylsulfonamido,diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl,arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl,heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl,heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl,alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy,cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl,lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy,hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, alkylenylamino,hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy,aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl,heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl,heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl,carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido,arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboxy,carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy,phosphono, phosphonoalkyl, diaralkoxyphosphono, anddiaralkoxyphosphonoalkyl;

R¹⁶, R¹⁹, R³², R³³, R³⁴, R³⁵, and R³⁶ are independently optionally Q^(b)with the proviso that no more than one of R¹⁶ and R¹⁹ is Q^(b) at thesame time and that Q^(b) is Q^(be);

B is optionally selected from the group consisting of hydrido,trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8alkynyl, C2-C8 haloalkyl, and C3-C8 haloalkenyl wherein each member ofgroup B is optionally substituted at any carbon up to and including 6atoms from the point of attachment of B to A with one or more of thegroup consisting of R³², R³³, R³⁴, R³⁵, and R³⁶;

B is optionally selected from the group consisting of C3-C12 cycloalkyl,C5-C10 cycloalkenyl, and C4-C9 saturated heterocyclyl, wherein each ringcarbon is optionally substituted with R³³, a ring carbon other than thering carbon at the point of attachment of B to A is optionallysubstituted with oxo provided that no more than one ring carbon issubstituted by oxo at the same time, ring carbon and nitrogen atomsadjacent to the carbon atom at the point of attachment is optionallysubstituted with R⁹ or R¹³, a ring carbon or nitrogen atom adjacent tothe R⁹ position and two atoms from the point of attachment is optionallysubstituted with R¹⁰, a ring carbon or nitrogen atom adjacent to the R¹³position and two atoms from the point of attachment is optionallysubstituted with R¹², a ring carbon or nitrogen atom three atoms fromthe point of attachment and adjacent to the R¹⁰ position is optionallysubstituted with R¹¹, a ring carbon or nitrogen atom three atoms fromthe point of attachment and adjacent to the R¹² position is optionallysubstituted with R³³, and a ring carbon or nitrogen atom four atoms fromthe point of attachment and adjacent to the R¹¹ and R³³ positions isoptionally substituted with R³⁴;

A is selected from the group consisting of single covalent bond,(W⁷)_(rr)—(CH(R¹⁵))_(pa) and (CH(R¹⁵))_(pa)—(W⁷)_(rr) wherein rr is aninteger selected from 0 through 1, pa is an integer selected from 0through 6, and W⁷ is selected from the group consisting of O, S, C(O),C(O)N(R⁷), C(S)N(R⁷), (R⁷)NC(O), (R⁷)NC(S), and N(R⁷) with the provisothat no more than one of the group consisting of rr and pa can be 0 atthe same time;

R⁷ and R⁸ are independently selected from the group consisting ofhydrido, hydroxy, alkyl, and alkoxyalkyl;

R¹⁴, R¹⁵, R³⁷, and R³⁸ are independently selected from the groupconsisting of hydrido, hydroxy, halo, alkyl, alkoxyalkyl, haloalkyl,haloalkoxy, and haloalkoxyalkyl;

R¹⁴ and R³⁸ can be independently selected from the group consisting ofaroyl and heteroaroyl;

Ψ is selected from the group consisting of NR⁵, C(O), and S(O)₂;

R⁵ is selected from the group consisting of hydrido, hydroxy, alkyl, andalkoxy;

R³⁹ and R⁴⁰ are independently selected from the group consisting ofhydrido, hydroxy, halo, hydroxyalkyl, alkyl, alkoxyalkyl, haloalkyl,haloalkoxy, and haloalkoxyalkyl;

M is selected from the group consisting of N and R¹—C;

R¹ is selected from the group consisting of hydrido, alkyl, alkenyl,cyano, halo, haloalkyl, haloalkoxy, haloalkylthio, amino, aminoalkyl,alkylamino, amidino, guanidino, hydroxy, hydroxyamino, alkoxy,hydroxyalkyl, alkoxyamino, thiol, alkylthio, and phosphono;

R² is Z⁰—Q;

Z⁰ is selected from the group consisting of covalent single bond,(CR⁴¹R⁴²)_(q) wherein q is an integer selected from 1 through 3,(CH(R⁴¹))_(g)—W⁰—(CH(R⁴²))_(p) wherein g and p are integersindependently selected from 0 through 3 and W⁰ is selected from thegroup consisting of O, S, C(O), S(O), S(O)₂, N(R⁴¹), and ON(R⁴¹), and(CH(R⁴¹))_(e)—W²²—(CH(R⁴²))_(h) wherein e and h are integersindependently selected from 0 through 2 and W²² is selected from thegroup consisting of CR⁴¹═CR⁴², 1,2-cyclopropyl, 1,2-cyclobutyl,1,2-cyclohexyl, 1,3-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl,2,3-morpholinyl, 2,4-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl,3,5-morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 2,3-piperazinyl,2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 2,3-piperidinyl,2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 1,2-pyrrolidinyl,1,3-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl,3,4-pyrrolidinyl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl,2,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the proviso thatZ⁰ is directly bonded to the pyrimidinone ring;

R⁴¹ and R⁴² are independently selected from the group consisting ofamidino, hydroxyamino, hydrido, hydroxy, amino, and alkyl;

Q is selected from the group consisting of hydrido, with the provisothat Z⁰ is other than a covalent single bond, the formula (II):

 wherein D¹, D², J¹, J² and K¹ are independently selected from the groupconsisting of C, N, O, S and a covalent bond with the provisos that nomore than one is a covalent bond, no more than one of D¹, D², J¹, J² andK¹ is O, no more than one of D¹, D², J¹, J² and K¹ is S, one of D¹, D²,J¹, J² and K¹ must be a covalent bond when two of D¹, D², J¹, J² and K¹are O and S, and no more than four of D¹, D², J¹, J² and K¹ is N, withthe proviso that R⁹, R¹⁰, R¹¹, R¹², and R¹³ are each independentlyselected to maintain the tetravalent nature of carbon, trivalent natureof nitrogen, the divalent nature of sulfur, and the divalent nature ofoxygen;

K is (CR^(4a)R^(4b))_(n) wherein n is an integer selected from 1 through2;

R^(4a) and R^(4b) are independently selected from the group consistingof halo, hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, andhaloalkyl;

E⁰ is selected from the group consisting of a covalent single bond,C(O), C(S), C(O)N(R⁷), (R⁷)NC(O), S(O)₂, (R⁷)NS(O)₂, and S(O)₂N(R⁷);

Y⁰ is formula (IV):

 wherein D⁵, D⁶, J⁵, and J⁶ are independently selected from the groupconsisting of C, N, O, S and a covalent bond with the provisos that nomore than one is a covalent bond, K² is C, no more than one of D⁵, D⁶,J⁵, and J⁶ is O, no more than one of D⁵, D⁶, J⁵, and J⁶ is S, one of D⁵,D⁶, J⁵, and J⁶ must be a covalent bond when two of D⁵, D⁶, J⁵, and J⁶are O and S, and no more than four of D⁵, D⁶, J⁵, and J⁶ are N when K²is carbon with the provisos that R¹⁶, R¹⁷, R¹⁸, and R¹⁹ are eachindependently selected to maintain the tetravalent nature of carbon,trivalent nature of nitrogen, the divalent nature of sulfur, and thedivalent nature of oxygen;

Q^(b) is selected from the group consisting of NR²⁰R²¹, ⁺NR²⁰R²¹R²²,aminoalkylenyl, and Q^(be), wherein Q^(be) is hydrido and R²⁰, R²¹, andR²² are independently selected from the group consisting of hydrido,alkyl, hydroxy, amino, aminoalkylenyl, dialkylamino, alkylamino, andhydroxyalkyl with the proviso that no more than one of R²⁰ and R²¹ ishydroxy, amino, alkylamino, or dialkylamino at the same time;

Q^(b) is optionally selected from the group consisting ofC(NR²⁵)NR²³R²⁴, N(R²⁶)C(NR²⁵)N(R²³)(R²⁴), C(O)N(R²⁶)C(NR²⁵)N(R²³)(R²⁴),N(R²⁶)N(R²⁶)C(NR²⁵)R²³)(R²⁴), and ON(R²⁶)C(NR²⁵)N(R²³)(R²⁴) with theprovisos that no more than one of R²³, R²⁴, and R²⁶ is hydroxy,alkylamino, amino, or dialkylamino when two of the group consisting ofR²³, R²⁴, and R²⁶ are bonded to the same atom;

R²³, R²⁴, R²⁵, and R²⁶ are independently selected from the groupconsisting of hydrido, alkyl, hydroxy, amino, alkylenylamino,dialkylamino, alkylamino, and hydroxyalkyl;

Q^(s) is selected from the group consisting of a single covalent bond,(CR³⁷R³⁸)_(b)—(W⁰)_(az) wherein az is an integer selected from 0 through1, b is an integer selected from 1 through 5, and W⁰ is selected fromthe group consisting of O, C(O), S(O), S(O)₂, S(O)₂N(R¹⁴), N(R¹⁴)S(O)₂,and N(R¹⁴), (CH(R¹⁴))_(c)—W¹—(CH(R¹⁵))_(d) wherein c and d are integersindependently selected from 1 through 4 and W¹ is selected from thegroup consisting of O, S, C(O), C(S), C(O)O, C(S)O, C(O)S, C(S)S,C(O)N(R¹⁴), (R¹⁴)NC(O), C(S)N(R¹⁴), (R¹⁴)NC(S), OC(O)N(R¹⁴),(R¹⁴)NC(O)O, SC(S)N(R¹⁴), (R¹⁴)NC(S)S, SC(O)N(R¹⁴), (R¹⁴)NC(O)S,OC(S)N(R¹⁴), (R¹⁴)NC(S)O, N(R¹⁵)C(O)N(R¹⁴), (R¹⁴)NC(O)N(R¹⁵),N(R¹⁵)C(S)N(R¹⁴), (R¹⁴)NC(S)N(R¹⁵), S(O), S(O)₂, S(O)₂N(R¹⁴),N(R¹⁴)S(O)₂, P(O)(R⁸), N(R⁷)P(O)(R⁸), P(O)(R⁸)N(R⁷), N(R¹⁴), ON(R¹⁴),and (CH(R¹⁴))_(e)—W²²—(CH(R¹⁵))_(h) wherein e and h are integersindependently selected from 0 through 2 and W²² is selected from thegroup consisting of CR⁴¹═CR⁴², CR⁴¹R⁴²═C; vinylidene), ethynylidene(C≡C; 1,2-ethynyl), 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl,1,3-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl,2,4-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl,1,2-piperazinyl, 1,3-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl,1,2-piperidinyl, 1,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl,2,6-piperidinyl, 3,4-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl,2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl,2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, and3,4-tetrahydrofuranyl, with the provisos that R¹⁴ and R¹⁵ are selectedfrom other than halo and cyano when directly bonded to N and that(CR³⁷R³⁸)_(b), (CH(R¹⁴))_(c), and (CH(R¹⁴))_(e) are bonded to E⁰;

Y⁰ is optionally Q^(b)—Q^(ss) wherein Q^(ss) is selected from the groupconsisting of (CR³⁷R³⁸)_(f) wherein f is an integer selected from 1through 4, (CH(R¹⁴))_(c)—W¹—(CH(R¹⁵))_(d) wherein c and d are integersindependently selected from 1 through 2, and W¹ is selected from thegroup consisting of W¹ is selected from the group consisting of O, S,C(O), C(O)N(R¹⁴), (R¹⁴)NC(O), N(R¹⁵)C(O)N(R¹⁴), (R¹⁴)NC(O)N(R¹⁵),N(R¹⁴), ON(R¹⁴), and (CH(R¹⁴))_(e)—W²—(CH(R¹⁵))_(h) wherein e and h areintegers independently selected from 0 through 2 and W² is selected fromthe group consisting of CR^(4a)═CR^(4b), ethynylidene (C≡C;1,2-ethynyl), and C═CR^(4a)R^(4b) with the provisos that R¹⁴ and R¹⁵ areselected from other than halo when directly bonded to N and that(CR³⁷R³⁸)_(f), (CH(R¹⁴))_(c), and (CH(R¹⁴))_(e) are bonded to E⁰;

Y⁰ is opionally Q^(b)—Q^(sss) wherein Q^(sss) is (CH(R³⁸))_(r)—W³, r isan integer selected from 1 through 2, W³ is selected from the groupconsisting of 1,1-cyclopropyl, 1,2-cyclopropyl, 1,1-cyclobutyl,1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl,1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl,2,5-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl,1,2-piperazinyl, 1,3-piperazinyl, 1,4-piperazinyl, 2,3-piperazinyl,2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl,1,4-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,5-piperidinyl,2,6-piperidinyl, 3,4-piperidinyl, 3,5-piperidinyl, 3,6-piperidinyl,1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl,2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2H-2,3-pyranyl, 2H-2,4-pyranyl,2H-2,5-pyranyl, 4H-2,3-pyranyl, 4H-2,4-pyranyl, 4H-2,5-pyranyl,2H-pyran-2-one-3,4-yl, 2H-pyran-2-one-4,5-yl, 4H-pyran-4-one-2,3-yl,2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl,3,4-tetrahydrofuranyl, 2,3-tetrahydropyranyl, 2,4-tetrahydropyranyl,2,5-tetrahydropyranyl, 2,6-tetrahydropyranyl, 3,4-tetrahydropyranyl, and3,5-tetrahydropyranyl, and each carbon and hyrido containing nitrogenmember of the ring of the W³ other than the points of attachment isoptionally substituted with one or more of the group consisting of R⁹,R¹⁰, R¹¹, and R¹², with the proviso that (CH(R³⁸))_(r) is bonded to E⁰and Q^(b) is bonded to lowest numbered substituent position of each W³;

Y⁰ is optionally Q^(b)—Q^(sssr) wherein Q^(sssr) is (CH(R³⁸))_(r)—W⁴, ris an integer selected from 1 through 2, W⁴ is selected from the groupconsisting of 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl,1,4-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl,2,4-morpholinyl, 2,5-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl,3,5-morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 1,4-piperazinyl,2,3-piperazinyl, 2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl,1,3-piperidinyl, 1,4-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl,2,5-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 3,5-piperidinyl,3,6-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl,2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2H-2,3-pyranyl,2H-2,4-pyranyl, 2H-2,5-pyranyl, 4H-2,3-pyranyl, 4H-2,4-pyranyl,4H-2,5-pyranyl, 2H-pyran-2-one-3,4-yl, 2H-pyran-2-one-4,5-yl,4H-pyran-4-one-2,3-yl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl,2,5-tetrahydrofuranyl, 3,4-tetrahydrofuranyl, 2,3-tetrahydropyranyl,2,4-tetrahydropyranyl, 2,5-tetrahydropyranyl, 2,6-tetrahydropyranyl,3,4-tetrahydropyranyl, and 3,5-tetrahydropyranyl, and each carbon andhyrido containing nitrogen member of the ring of the W⁴ other than thepoints of attachment is optionally substituted with one or more of thegroup consisting of R⁹, R¹⁰, R¹¹, and R¹², with the provisos that(CH(R³⁸))_(r) is bonded to E⁰ and Q^(b) is bonded to highest numbersubstituent position of each W⁴;

Y⁰ is optionally Q^(b)—Q^(ssss) wherein Q^(ssss) is (CH(R³⁸))_(r)—W⁵, ris an integer selected from 1 through 2, W⁵ is selected from the groupconsisting of 1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7-indenyl,2,7-indenyl, 2,6-indenyl, 2,5-indenyl, 2,4-indenyl, 3,4-indenyl,3,5-indenyl, 3,6-indenyl, 3,7-indenyl, 2,4-benzofuranyl,2,5-benzofuranyl, 2,6-benzofuranyl, 2,7-benzofuranyl, 3,4-benzofuranyl,3,5-benzofuranyl, 3,6-benzofuranyl, 3,7-benzofuranyl,2,4-benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl,2,7-benzothiophenyl, 3,4-benzothiophenyl, 3,5-benzothiophenyl,3,6-benzothiophenyl, 3,7-benzothiophenyl, 2,7-imidazo(1,2-a)pyridinyl,3,4-imidazo(1,2-a)pyridinyl, 3,5-imidazo(1,2-a)pyridinyl,3,6-imidazo(1,2-a)pyridinyl, 3,7-imidazo(1,2-a)pyridinyl, 2,4-indolyl,2,5-indolyl, 2,6-indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl,3,6-indolyl, 3,7-indolyl, 1,4-isoindolyl, 1,5-isoindolyl,1,6-isoindolyl, 2,4-isoindolyl, 2,5-isoindolyl, 2,6-isoindolyl,2,7-isoindolyl, 1,3-isoindolyl, 3,4-indazolyl, 3,5-indazolyl,3,6-indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl, 2,5-benzoxazolyl,2,6-benzoxazolyl, 2,7-benzoxazolyl, 3,4-benzisoxazolyl,3,5-benzisoxazolyl, 3,6-benzisoxazolyl, 3,7-benzisoxazolyl,1,4-naphthyl, 1,5-naphthyl, 1,6-naphthyl, 1,7-naphthyl, 1,8-naphthyl,2,4-naphthyl, 2,5-naphthyl, 2,6-naphthyl, 2,7-naphthyl, 2,8-naphthyl,2,4-quinolinyl, 2,5-quinolinyl, 2,6-quinolinyl, 2,7-quinolinyl,2,8-quinolinyl, 3,4-quinolinyl, 3,5-quinolinyl, 3,6-quinolinyl,3,7-quinolinyl, 3,8-quinolinyl, 4,5-quinolinyl, 4,6-quinolinyl,4,7-quinolinyl, 4,8-quinolinyl, 1,4-isoquinolinyl, 1,5-isoquinolinyl,1,6-isoquinolinyl, 1,7-isoquinolinyl, 1,8-isoquinolinyl,3,4-isoquinolinyl, 3,5-isoquinolinyl, 3,6-isoquinolinyl,3,7-isoquinolinyl, 3,8-isoquinolinyl, 4,5-isoquinolinyl,4,6-isoquinolinyl, 4,7-isoquinolinyl, 4,8-isoquinolinyl, 3,4-cinnolinyl,3,5-cinnolinyl, 3,6-cinnolinyl, 3,7-cinnolinyl, 3,8-cinnolinyl,4,5-cinnolinyl, 4,6-cinnolinyl, 4,7-cinnolinyl, and 4,8-cinnolinyl, andeach carbon and hyrido containing nitrogen member of the ring of the W⁵other than the points of attachment is optionally substituted with oneor more of the group consisting of R⁹, R¹⁰, R¹¹, and R¹², with theproviso that Q^(b) is bonded to lowest number substituent position ofeach W⁵ and that (CH(R³⁸))_(r) is bonded to E⁰;

Y⁰ is optionally Q^(b)—Q^(ssssr) wherein Q^(ssssr) is (CH(R³⁸))_(r)—W⁶,r is an integer selected from 1 through 2, W⁶ is selected from the groupconsisting of 1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7-indenyl,2,7-indenyl, 2,6-indenyl, 2,5-indenyl, 2,4-indenyl, 3,4-indenyl,3,5-indenyl, 3,6-indenyl, 3,7-indenyl, 2,4-benzofuranyl,2,5-benzofuranyl, 2,6-benzofuranyl, 2,7-benzofuranyl, 3,4-benzofuranyl,3,5-benzofuranyl, 3,6-benzofuranyl, 3,7-benzofuranyl,2,4-benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl,2,7-benzothiophenyl, 3,4-benzothiophenyl, 3,5-benzothiophenyl,3,6-benzothiophenyl, 3,7-benzothiophenyl, 2,7-imidazo(1,2-a)pyridinyl,3,4-imidazo(1,2-a)pyridinyl, 3,5-imidazo(1,2-a)pyridinyl,3,6-imidazo(1,2-a)pyridinyl, 3,7-imidazo(1,2-a)pyridinyl, 2,4-indolyl,2,5-indolyl, 2,6-indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl,3,6-indolyl, 3,7-indolyl, 1,4-isoindolyl, 1,5-isoindolyl,1,6-isoindolyl, 2,4-isoindolyl, 2,5-isoindolyl, 2,6-isoindolyl,2,7-isoindolyl, 1,3-isoindolyl, 3,4-indazolyl, 3,5-indazolyl,3,6-indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl, 2,5-benzoxazolyl,2,6-benzoxazolyl, 2,7-benzoxazolyl, 3,4-benzisoxazolyl,3,5-benzisoxazolyl, 3,6-benzisoxazolyl, 3,7-benzisoxazolyl,1,4-naphthyl, 1,5-naphthyl, 1,6-naphthyl, 1,7-naphthyl, 1,8-naphthyl,2,4-naphthyl, 2,5-naphthyl, 2,6-naphthyl, 2,7-naphthyl, 2,8-naphthyl,2,4-quinolinyl, 2,5-quinolinyl, 2,6-quinolinyl, 2,7-quinolinyl,2,8-quinolinyl, 3,4-quinolinyl, 3,5-quinolinyl, 3,6-quinolinyl,3,7-quinolinyl, 3,8-quinolinyl, 4,5-quinolinyl, 4,6-quinolinyl,4,7-quinolinyl, 4,8-quinolinyl, 1,4-isoquinolinyl, 1,5-isoquinolinyl,1,6-isoquinolinyl, 1,7-isoquinolinyl, 1,8-isoquinolinyl,3,4-isoquinolinyl, 3,5-isoquinolinyl, 3,6-isoquinolinyl,3,7-isoquinolinyl, 3,8-isoquinolinyl, 4,5-isoquinolinyl,4,6-isoquinolinyl, 4,7-isoquinolinyl, 4,8-isoquinolinyl, 3,4-cinnolinyl,3,5-cinnolinyl, 3,6-cinnolinyl, 3,7-cinnolinyl, 3,8-cinnolinyl,4,5-cinnolinyl, 4,6-cinnolinyl, 4,7-cinnolinyl, and 4,8-cinnolinyl, andeach carbon and hyrido containing nitrogen member of the ring of the W⁶other than the points of attachment is optionally substituted with oneor more of the group consisting of R⁹, R¹⁰, R¹¹, and R¹², with theproviso that Q^(b) is bonded to highest number substituent position ofeach W⁶ and that (CH(R³⁸))_(r) is bonded to E⁰.

In a preferred embodiment of compounds of Formula I or apharmaceutically acceptable salt thereof,

J is O;

B is the Formula:

R⁹, R¹⁰, R¹¹, R¹², R¹³, R³², R³³, R³⁴, R³⁵, and R³⁶ are independentlyselected from the group consisting of hydrido, acetamido, haloacetamido,amidino, guanidino, alkylenedioxy, haloalkylthio, alkanoyloxy, alkoxy,alkoxyalkyl, haloalkoxylalkyl, hydroxy, amino, alkoxyamino, nitro, loweralkylamino, alkylthio, alkylthioalkyl, alkylsulfinyl, alkylsulfonyl,alkylsulfonylalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,alkylsulfonamnido, alkylaminosulfonyl, amidosulfonyl, monoalkylamidosulfonyl, dialkyl amidosulfonyl, alkanoyl, haloalkanoyl, alkyl,alkenyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl,hydroxyalkyl, aminoalkyl, haloalkoxyalkyl, carboxyalkyl, carboalkoxy,carboxy, carboxamido, carboxamidoalkyl, and cyano;

R⁹, R¹⁰, R¹¹, R¹², and R¹³ are optionally selected from the groupconsisting of heteroaryl and heterocyclyl with the proviso that R⁹, R¹⁰,R¹¹, R¹², and R¹³ are substitutents for other than B;

R¹⁶, R¹⁹, R³², R³³, R³⁴, R³⁵, and R³⁶ are independently optionally Q^(b)with the proviso that no more than one of R¹⁶ and R¹⁹ is Q^(b) at thesame time and that Q^(b) is Q^(be);

B is optionally selected from the group consisting of hydrido,trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8alkynyl, and C2-C8 haloalkyl, wherein each member of group B may beoptionally substituted at any carbon up to and including 6 atoms fromthe point of attachment of B to A with one or more of the groupconsisting of R³², R³³ R³⁴, R³⁵, and R³⁶;

B is selected from the group consisting of C3-C12 cycloalkyl andC4-heterocyclyl, wherein each ring carbon may be optionally substitutedwith R³³, a ring carbon other than the ring carbon at the point ofattachment of B to A may be optionally substituted with oxo providedthat no more than one ring carbon is substituted by oxo at the sametime, ring carbons and a nitrogen adjacent to the carbon at the point ofattachment may be optionally substituted with R⁹ or R¹³, a ring carbonor nitrogen adjacent to the R⁹ position and two atoms from the point ofattachment may be substituted with R¹⁰, a ring carbon or nitrogenadjacent to the R¹³ position and two atoms from the point of attachmentmay be substituted with R¹², a ring carbon or nitrogen three atoms fromthe point of attachment and adjacent to the R¹⁰ position may besubstituted with R¹¹, a ring carbon or nitrogen three atoms from thepoint of attachment and adjacent to the R¹² position may be substitutedwith R³³, and a ring carbon or nitrogen four atoms from the point ofattachment and adjacent to the R¹¹ and R³³ positions may be substitutedwith R³⁴;

A is selected from the group consisting of single covalent bond,(W⁷)_(rr)—(CH(R¹⁵))_(pa) and (CH(R¹⁵))_(pa)—(W⁷)_(rr) wherein rr is aninteger selected from 0 through 1, pa is an integer selected from 0through 6, and W⁷ is selected from the group consisting of O, S, C(O),(R⁷)NC(O), (R⁷)NC(S), and N(R⁷) with the proviso that no more than oneof the group consisting of rr and pa is 0 at the same time;

R⁷ is selected from the group consisting of hydrido, hydroxy, and alkyl;

R¹⁵ is selected from the group consisting of hydrido, hydroxy, halo,alkyl, and haloalkyl;

Ψ is selected from the group consisting of NH and NOH;

M is selected from the group consisting of N and R¹—C;

R¹ is selected from the group consisting of hydrido, alkyl, alkenyl,cyano, halo, haloalkyl, haloalkoxy, haloalkylthio, amino, aminoalkyl,alkylamino, amidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl,alkoxyamino, thiol, and alkylthio;

R² is Z⁰—Q;

Z⁰ is selected from the group consisting of covalent single bond,(CR⁴¹R⁴²)_(q) wherein q is an integer selected from 1 through 3,(CH(R⁴¹))_(g)—W⁰—(CH(R⁴²))_(p) wherein g and p are integersindependently selected from 0 through 3 and W⁰ is selected from thegroup consisting of O, S, C(O), S(O), N(R⁴¹), and ON(R⁴¹), and(CH(R⁴¹))_(e)—W²²—(CH(R⁴²))_(h) wherein e and h are integersindependently selected from 0 through 1 and W²² is selected from thegroup consisting of CR⁴¹═CR⁴², 1,2-cyclopropyl, 1,2-cyclobutyl,1,2-cyclohexyl, 1,3-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl,2,3-morpholinyl, 2,4-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl,3,5-morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 2,3-piperazinyl,2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 2,3-piperidinyl,2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 1,2-pyrrolidinyl,1,3-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl,3,4-pyrrolidinyl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl,2,5-stetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the proviso thatZ⁰ is directly bonded to the pyrimidinone ring;

R⁴¹ and R⁴² are independently selected from the group consisting ofamidino, hydroxyamino, hydrido, hydroxy, amino, and alkyl;

Q^(b) is selected from the group consisting of hydrido, with the provisothat Z⁰ is other than a covalent single bond, and the formula (II):

 wherein D¹, D², J¹, J² and K¹ are independently selected from the groupconsisting of C, N, O, S and a covalent bond with the provisos that nomore than one is a covalent bond, no more than one of D¹, D², J¹, J₂ andK¹ is O, no more than one of D¹, D², J¹, J² and K¹ is S, one of D¹, D²,J¹, J² and K¹ must be a covalent bond when two of D¹, D², J¹, J² and K¹are O and S, and no more than four of D¹, D², J¹, J² and K¹ are N, withthe proviso that R⁹, R¹⁰, R¹¹, R¹², and R¹³ are each independentlyselected to maintain the tetravalent nature of carbon, trivalent natureof nitrogen, the divalent nature of sulfur, and the divalent nature ofoxygen;

K¹ is (CR^(4a)R^(4b))_(n) wherein n is an integer selected from 1through 2;

R^(4a) and R^(4b) are independently selected from the group consistingof halo, hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, andhaloalkyl;

E⁰ is E¹, when K is (CR^(4a)R^(4b))_(n), wherein E¹ is selected from thegroup consisting of a covalent single bond, C(O), C(S), C(O)N(R⁷),(R⁷)NC(O), S(O)₂, (R⁷)NS(O)₂, and S(O)₂N(R⁷);

Y⁰ is formula (IV):

 wherein D⁵, D⁶, J⁵, and J⁶ are independently selected from the groupconsisting of C, N, O, S and a covalent bond with the provisos that nomore than one is a covalent bond, K² is C, no more than one of D⁵, D⁶,J⁵, and J⁶ is O, no more than one of D⁵, D⁶, J⁵, and J⁶ is S, one of D⁵,D⁶, J⁵, and J⁶ must be a covalent bond when two of D⁵, D⁶, J⁵, and J⁶are O and S, and no more than four of D⁵, D⁶, J⁵, and J⁶ are N with theproviso that R¹⁶, R¹⁷, R¹⁸, and R¹⁹ are each independently selected tomaintain the tetravalent nature of carbon, trivalent nature of nitrogen,the divalent nature of sulfur, and the divalent nature of oxygen;

R¹⁶, R¹⁷, R¹⁸, and R¹⁹ are independently selected from the groupconsisting of hydrido, amidino, guanidino, carboxy, haloalkylthio,alkoxy, hydroxy, amino, nitro, alkoxyamino, lower alkylamino, alkylthio,alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, alkenyl,halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkylenylamino,haloalkoxyalkyl, carboalkoxy, and cyano;

Q^(b) is selected from the group consisting of NR²⁰R²¹, aminoalkylenyl,Q^(be) wherein Q^(be) is hydrido, N(R²⁶)C(NR²⁵)N(R²³)(R²⁴), andC(NR²⁵)NR²³R²⁴, with the provisos that no more than one of R²⁰ and R²¹is hydroxy, amino, alkylamino, or dialkylamino at the same time and thatno more than one of R²³ and R²⁴ is hydroxy, amino, alkylamino, ordialkylamino at the same time;

R²⁰, R²¹, R²³, R²⁴, R²⁵, and R²⁶ are independently selected from thegroup consisting of hydrido, alkyl, hydroxy, aminoalkylenyl, amino,dialkylamino, alkylamino, and hydroxyalkyl;

Q^(s) is selected from the group consisting of a single covalent bond,(CR³⁷R³⁸)_(b) wherein b is an integer selected from 1 through 4, and(CH(R¹⁴))_(c)—W¹—(CH(R¹⁵))_(d) wherein c and d are integersindependently selected from 1 through 3 and W¹ is selected from thegroup consisting of C(O)N(R¹⁴), (R¹⁴)NC(O), S(O), S(O)₂, S(O)₂N(R¹⁴),N(R¹⁴)S(O)₂, and N(R¹⁴), with the provisos that R¹⁴ is selected fromother than halo when directly bonded to N and that (CR³⁷R³⁸)_(b), and(CH(R¹⁴))_(c) are bonded to E⁰;

R¹⁴ is selected from the group consisting of hydrido, halo, alkyl, andhaloalkyl;

R³⁷ and R³⁸ are independently selected from the group consisting ofhydrido, alkyl, and haloalkyl;

R³⁸ is optionally selected from the group consisting of aroyl andheteroaroyl;

Y⁰ is optionally Q^(b)—Q^(ss) wherein Q^(ss) is(CH(R¹⁴))_(e)—W²—(CH(R¹⁵))_(h), wherein e and h are integersindependently selected from 1 through 2 and W² is CR^(4a)═CR^(4b) withthe proviso that (CH(R¹⁴))_(e) is bonded to E⁰;

Y⁰ is optionally selected from the group consisting of Q^(b)—Q^(ssss)and Q^(b)—Q^(ssssr) wherein Q^(ssss) is (CH(R³⁸))_(r)—W⁵ and Q^(ssssr)is (CH(R³⁸))_(r)—W⁶, r is an integer selected from 1 through 2, and W⁵and W⁶ are independently selected from the group consisting of1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7-indenyl, 2,7-indenyl,2,6-indenyl, 2,5-indenyl, 2,4-indenyl, 3,4-indenyl, 3,5-indenyl,3,6-indenyl, 3,7-indenyl, 2,4-benzofuranyl, 2,5-benzofuranyl,2,6-benzofuranyl, 2,7-benzofuranyl, 3,4-benzofuranyl, 3,5-benzofuranyl,3,6-benzofuranyl, 3,7-benzofuranyl, 2,4-benzothiophenyl,2,5-benzothiophenyl, 2,6-benzothiophenyl, 2,7-benzothiophenyl,3,4-benzothiophenyl, 3,5-benzothiophenyl, 3,6-benzothiophenyl,3,7-benzothiophenyl, 2,7-imidazo(1,2-a)pyridinyl,3,4-imidazo(1,2-a)pyridinyl, 3,5-imidazo(1,2-a)pyridinyl,3,6-imidazo(1,2-a)pyridinyl, 3,7-imidazo(1,2-a)pyridinyl, 2,4-indolyl,2,5-indolyl, 2,6-indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl,3,6-indolyl, 3,7-indolyl, 1,4-isoindolyl, 1,5-isoindolyl,1,6-isoindolyl, 2,4-isoindolyl, 2,5-isoindolyl, 2,6-isoindolyl,2,7-isoindolyl, 1,3-isoindolyl, 3,4-indazolyl, 3,5-indazolyl,3,6-indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl, 2,5-benzoxazolyl,2,6-benzoxazolyl, 2,7-benzoxazolyl, 3,4-benzisoxazolyl,3,5-benzisoxazolyl, 3,6-benzisoxazolyl, 3,7-benzisoxazolyl,1,4-naphthyl, 1,5-naphthyl, 1,6-naphthyl, 1,7-naphthyl, 1,8-naphthyl,2,4-naphthyl, 2,5-naphthyl, 2,6-naphthyl, 2,7-naphthyl, 2,8-naphthyl,2,4-quinolinyl, 2,5-quinolinyl, 2,6-quinolinyl, 2,7-quinolinyl,2,8-quinolinyl, 3,4-quinolinyl, 3,5-quinolinyl, 3,6-quinolinyl,3,7-quinolinyl, 3,8-quinolinyl, 4,5-quinolinyl, 4,6-quinolinyl,4,7-quinolinyl, 4,8-quinolinyl, 1,4-isoquinolinyl, 1,5-isoquinolinyl,1,6-isoquinolinyl, 1,7-isoquinolinyl, 1,8-isoquinolinyl,3,4-isoquinolinyl, 3,5-isoquinolinyl, 3,6-isoquinolinyl,3,7-isoquinolinyl, 3,8-isoquinolinyl, 4,5-isoquinolinyl,4,6-isoquinolinyl, 4,7-isoquinolinyl, 4,8-isoquinolinyl, 3,4-cinnolinyl,3,5-cinnolinyl, 3,6-cinnolinyl, 3,7-cinnolinyl, 3,8-cinnolinyl,4,5-cinnolinyl, 4,6-cinnolinyl, 4,7-cinnolinyl, and 4,8-cinnolinyl, andeach carbon and hyrido containing nitrogen member of the ring of the W⁵and of the ring of the W⁶, other than the points of attachment of W⁵ andW⁶, is optionally substituted with one or more of the group consistingof R⁹, R¹⁰, R¹¹, and R¹², with the provisos that Q^(b) is bonded tolowest number substituent position of each W⁵, Q^(b) is bonded tohighest number substituent position of each W⁶, and (CH(R³⁸))_(r) isbonded to E⁰.

In a more preferred embodiment of compounds of Formula I or apharmaceutically acceptable salt thereof,

J is O;

B is the Formula:

R³², R³³, R³⁴, R³⁵, and R³⁶ are independently selected from the groupconsisting of hydrido, acetamido, haloacetamido, amidino, guanidino,alkylenedioxy, haloalkylthio, alkanoyloxy, alkoxy, hydroxy, amino,alkoxyamino, alkanoyl, haloalkanoyl, nitro, lower alkylamino, alkylthio,aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkylsulfonamido,amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl,alkenyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyalkyl,alkylenylamino, carboalkoxy, carboxy, carboxamido, cyano, and Q^(b);

B is optionally selected from the group consisting of hydrido,trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8alkynyl, and C2-C8 haloalkyl, wherein each member of group B isoptionally substituted at any carbon up to and including 6 atoms fromthe point of attachment of B to A with one or more of the groupconsisting of R³², R³³, R³⁴, R³⁵, and R³⁶;

B is selected from the group consisting of C3-C12 cycloalkyl andC4-heterocyclyl, wherein each ring carbon may be optionally substitutedwith R³³, a ring carbon other than the ring carbon at the point ofattachment of B to A may be optionally substituted with oxo providedthat no more than one ring carbon is substituted by oxo at the sametime, ring carbons and a nitrogen adjacent to the carbon at the point ofattachment may be optionally substituted with R⁹ or R¹³, a ring carbonor nitrogen adjacent to the R⁹ position and two atoms from the point ofattachment may be substituted with R¹⁰, a ring carbon or nitrogenadjacent to the R¹³ position and two atoms from the point of attachmentmay be substituted with R¹², a ring carbon three atoms from the point ofattachment and adjacent to the R¹⁰ position may be substituted with R¹¹,a ring carbon three atoms from the point of attachment and adjacent tothe R¹² position may be substituted with R³³, and a ring carbon fouratoms from the point of attachment and adjacent to the R¹¹ and R³³positions may be substituted with R³⁴;

R⁹, R¹⁰, R¹¹, R¹², and R¹³ are independently selected from the groupconsisting of hydrido, acetamido, haloacetamido, alkoxyamino, alkanoyl,haloalkanoyl, amidino, guanidino, alkylenedioxy, haloalkylthio, alkoxy,hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl,alkylsulfonyl, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl,dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl,aminoalkyl, carboalkoxy, carboxyalkyl, carboxy, carboxamido, and cyano;

R⁹, R¹⁰, R¹¹, R¹², and R¹³ are optionally selected from the groupconsisting of heteroaryl and heterocyclyl with the proviso that R⁹, R¹⁰,R¹¹, R¹², and R¹³ are substitutents for other than B;

A is selected from the group consisting of single covalent bond and(CH(R¹⁵))_(pa)—(W⁷)_(rr) wherein rr is an integer selected from 0through 1, pa is an integer selected from 0 through 3, and W⁷ isselected from the group consisting of O, S, C(O), (R⁷)NC(O), (R⁷)NC(S),and N(R⁷);

R⁷ is selected from the group consisting of hydrido, hydroxy and alkyl;

R¹⁵ is selected from the group consisting of hydrido, hydroxy, halo,alkyl, and haloalkyl;

Ψ is NH;

M is selected from the group consisting of N and R¹—C;

R¹ is selected from the group consisting of hydrido, alkyl, cyano, halo,haloalkyl, haloalkoxy, amino, aminoalkyl, alkylamino, amidino, hydroxy,hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, and alkylthio;

R² is Z⁰—Q;

Z⁰ is selected from the group consisting of covalent single bond and(CR⁴¹R⁴²) wherein q is an integer selected from 1 through 2,(CH(R⁴¹))_(g)—W⁰—(CH(R⁴²))_(p) wherein g and p are integersindependently selected from 0 through 3 and W⁰ is selected from thegroup consisting of O, S, and N(R⁴¹), and(CH(R⁴¹))_(e)—W²²—(CH(R⁴²))_(h) wherein e and h are integersindependently selected from 0 through 1 and W²² is selected from thegroup consisting of CR⁴¹═CR⁴², 1,2-cyclopropyl, 1,2-cyclobutyl,1,2-cyclohexyl, 1,3-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl,2,3-morpholinyl, 2,4-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl,3,5-morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 2,3-piperazinyl,2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 2,3-piperidinyl,2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 1,2-pyrrolidinyl,1,3-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl,3,4-pyrrolidinyl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl,2,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the proviso thatZ⁰ is directly bonded to the pyrimidinone ring;

R⁴¹ and R⁴² are independently selected from the group consisting ofhydrido, hydroxy, and amino; p1 Q^(b) is selected from the groupconsisting of hydrido, with the proviso that Z⁰ is other than a covalentsingle bond, aryl, and heteroaryl, wherein a carbon adjacent to thecarbon at the point of attachment is optionally substituted by R⁹, theother carbon adjacent to the carbon at the point of attachment isoptionally substituted by R¹³, a carbon adjacent to R⁹ and two atomsfrom the carbon at the point of attachment is optionally substituted byR¹⁰, a carbon adjacent to R¹³ and two atoms from the carbon at the pointof attachment is optionally substituted by R¹², and any carbon adjacentto both R¹⁰ and R¹² is optionally substituted by R¹¹;

K is CHR^(4a) wherein R^(4a) is selected from the group consisting ofhydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, andhaloalkyl;

E⁰ is selected from the group consisting of a covalent single bond,C(O)N(H), (H)NC(O), (R⁷)NS(O)₂, and S(O)₂N(R⁷);

Y⁰ is formula (IV):

 wherein D⁵, D⁶, J⁵, and J⁶ are independently selected from the groupconsisting of C, N, O, S and a covalent bond with the provisos that nomore than one is a covalent bond, K² is C, no more than one of D⁵, D⁶,J⁵, and J⁶ is O, no more than one of D⁵, D⁶, J⁵, and J⁶ is S, one of D⁵,D⁶, J⁵, and J⁶ must be a covalent bond when two of D⁵, D⁶, J⁵, and J⁶are O and S, and no more than four of D⁵, D⁶, J⁵, and J⁶ are N, with theprovisos that R¹⁶, R¹⁷, R¹⁸, and R¹⁹ are each independently selected tomaintain the tetravalent nature of carbon, trivalent nature of nitrogen,the divalent nature of sulfur, and the divalent nature of oxygen;

R¹⁶, R¹⁷, R¹⁸, and R¹⁹ are independently selected from the groupconsisting of hydrido, amidino, guanidino, carboxy, haloalkylthio,alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio,alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo,haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;

R¹⁶ and R¹⁹ are optionally Q^(b) with the proviso that no more than oneof R¹⁶ and R¹⁹ is Q^(b) at the same time and that Q^(b) is Q^(be);

Q^(b) is selected from the group consisting of NR²⁰R²¹, Q^(b) whereinQ^(be) is hydrido, N(R²⁶)C(NR²⁵)N(R²³)(R²⁴), and C(NR²⁵)NR²³R²⁴, withthe provisos that no more than one of R²⁰ and R²¹ is hydroxy, amino,alkylamino, or dialkylamino at the same time and that no more than oneof R²³ and R²⁴ is hydroxy, amino, alkylamino, or dialkylamino at thesame time;

R²⁰, R²¹, R²³, R²⁴, R²⁵, and R²⁶ are independently selected from thegroup consisting of hydrido, alkyl, hydroxy, amino, alkylamino anddialkylamino;

Q^(s) is selected from the group consisting of a single covalent bond,(CR³⁷R³⁸)_(b) wherein b is an integer selected from 1 through 4, and(CH(R¹⁴))_(c)—W¹—(CH(R¹⁵))_(d) wherein c and d are integersindependently selected from 1 through 3 and W¹ is selected from thegroup consisting of C(O)N(R¹⁴), (R¹⁴)NC(O), S(O), S(O)₂, S(O)₂N(R¹⁴),N(R¹⁴)S(O)₂, and N(R¹⁴), with the provisos that R¹⁴ is selected fromother than halo when directly bonded to N and that (CR³⁷R³⁸)_(b), and(CH(R¹⁴))_(c) are bonded to E⁰;

R¹⁴ is selected from the group consisting of hydrido, halo, alkyl, andhaloalkyl;

R³⁷ and R³⁸ are independently selected from the group consisting ofhydrido, alkyl, and haloalkyl;

R³⁸ is optionally selected from the group consisting of aroyl andheteroaroyl;

Y⁰ is optionally Q^(b)—Q^(ss) wherein Q^(ss) is(CH(R¹⁴))_(e)—W²—(CH(R¹⁵))_(h), wherein e and h are integersindependently selected from 1 through 2 and W² is CR^(4a)═CH with theproviso that (CH(R¹⁴))_(e) is bonded to E⁰.

In an even more preferred embodiment of compounds of Formula I or apharmaceutically acceptable salt thereof,

J is O;

B is the Formula:

R³², R³³, R³⁴, R³⁵, and R³⁶ are independently selected from the groupconsisting of hydrido, acetamido, haloacetamido, amidino, guanidino,alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio,amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl,halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy,carboxamido, cyano, and Q^(b);

A is selected from the group consisting of single covalent bond and(CH(R¹⁵))_(pa)—(W⁷)_(rr) wherein rr is an integer selected from 0through 1, pa is an integer selected from 0 through 3, and W⁷ isselected from the group consisting of(R⁷)NC(O) and N(R⁷);

R⁷ is selected from the group consisting of hydrido, hydroxy and alkyl;

R¹⁵ is selected from the group consisting of hydrido, halo, alkyl, andhaloalkyl;

Ψ is NH;

M is selected from the group consisting of N and R¹—C;

R¹ is selected from the group consisting of hydrido, hydroxy,hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl,alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy,and halo;

R² is Z⁰—Q;

Z⁰ is selected from the group consisting of a covalent single bond, O,S, NH, and CH₂;

Q^(b) is selected from the group consisting of aryl and heteroarylwherein a carbon adjacent to the carbon at the point of attachment isoptionally substituted by R⁹, the other carbon adjacent to the carbon atthe point of attachment is optionally substituted by R¹³, a carbonadjacent to R⁹ and two atoms from the carbon at the point of attachmentis optionally substituted by R¹⁰, a carbon adjacent to R¹³ and two atomsfrom the carbon at the point of attachment is optionally substituted byR¹², and any carbon adjacent to both R¹⁰ and R¹² is optionallysubstituted by R¹¹;

R⁹, R¹¹, and R¹³ are independently selected from the group consisting ofhydrido, hydroxy, amino, amidino, guanidino, lower alkylamino,alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl,amidosulfonyl, monoalkyl amidosulfonyl, alkyl, alkoxy, halo, haloalkyl,haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano;

R¹⁰ and R¹² are independently selected from the group consisting ofhydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy,hydroxy, amino, alkoxyamino, lower alkylamino, alkylsulfonamido,amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl,hydroxyalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl,amidocarbonyl, halo, haloalkyl, and cyano;

K is CH₂;

E⁰ is C(O)N(H);

Y⁰ is formula (IV):

 wherein D⁵, D⁶, J⁵, and J⁶ are independently selected from the groupconsisting of C, N, O, S and a covalent bond with the provisos that nomore than one is a covalent bond, K² is C, no more than one of D⁵, D⁶,J⁵, and J⁶ is optionally O, no more than one of D⁵, D⁶, J⁵, and J⁶ isoptionally S, one of D⁵, D⁶, J⁵, and J⁶ must be a covalent bond when twoof D⁵, D⁶, J⁵, and J⁶ are O and S, and no more than four of D⁵, D⁶, J⁵,and J⁶ are N;

R¹⁶, R¹⁷, R¹⁸, and R¹⁹ are independently selected from the groupconsisting of hydrido, amidino, guanidino, carboxy, haloalkylthio,alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl,alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl,haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;

R¹⁶ and R¹⁹ are optionally Q^(b) with the proviso that no more than oneof R¹⁶ and R¹⁹ is Q^(b) at the same time and that Q^(b) is Q^(be);

Q^(b) is selected from the group consisting of NR²⁰R²¹, Q^(be) whereinQ^(be) is hydrido, and C(NR²⁵)NR²³R²⁴, with the provisos that no morethan one of R²⁰ and R²¹ is hydroxy at the same time and that no morethan one of R²³ and R²⁴ is hydroxy at the same time;

R²⁰, R²¹, R²³, R²⁴, and R²⁵ are independently selected from the groupconsisting of hydrido, alkyl, and hydroxy;

Q^(s) is selected from the group consisting of a single covalent bond,CH₂, and CH₂CH₂.

In another even more preferred embodiment of compounds of Formula I or apharmaceutically acceptable salt thereof,

J is O;

B is optionally selected from the group consisting of hydrido, C2-C8alkyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein eachmember of group B is optionally substituted at any carbon up to andincluding 6 atoms from the point of attachment of B to A with one ormore of the group consisting of R³², R³³, R³⁴, R³⁵, and R³⁶;

R³², R³³, R³⁴, R³⁵, and R³⁶ are independently selected from the groupconsisting of hydrido, acetamido, haloacetamido, amidino, guanidino,alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio,amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl,halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy,carboxamido, cyano, and Q^(b);

A is selected from the group consisting of single covalent bond and(CH(R¹⁵))_(pa)—(W⁷)_(rr) wherein rr is an integer selected from 0through 1, pa is an integer selected from 0 through 3, and W⁷ isselected from the group consisting of (R⁷)NC(O) and N(R⁷);

R⁷ is selected from the group consisting of hydrido, hydroxy and alkyl;

R¹⁵ is selected from the group consisting of hydrido, halo, alkyl, andhaloalkyl;

Ψ is NH;

M is selected from the group consisting of N and R¹—C;

R¹ is selected from the group consisting of hydrido, hydroxy,hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl,alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy,and halo;

R² is Z⁰—Q;

Z⁰ is selected from the group consisting of covalent single bond, O, S,NH, and CH₂;

Q^(b) is selected from the group consisting of aryl and heteroarylwherein a carbon adjacent to the carbon at the point of attachment isoptionally substituted by R⁹, the other carbon adjacent to the carbon atthe point of attachment is optionally substituted by R¹³, a carbonadjacent to R⁹ and two atoms from the carbon at the point of attachmentis optionally substituted by R¹⁰, a carbon adjacent to R¹³ and two atomsfrom the carbon at the point of attachment is optionally substituted byR¹², and any carbon adjacent to both R¹⁰ and R¹² is optionallysubstituted by R¹¹;

R⁹, R¹¹, and R¹³ are independently selected from the group consisting ofhydrido, hydroxy, amino, amidino, guanidino, lower alkylamino,alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl,amidosulfonyl, monoalkyl amidosulfonyl, alkyl, alkoxy, halo, haloalkyl,haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano;

R¹⁰ and R¹² are independently selected from the group consisting ofhydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy,hydroxy, amino, alkoxyamino, lower alkylamino, alkylsulfonamido,amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl,hydroxyalkyl, alkylenylamino, carboalkoxy, carboxy, carboxyalkyl,amidocarbonyl, halo, haloalkyl, and cyano;

K is CH₂;

E⁰ is C(O)N(H);

Y⁰ is formula (IV):

 wherein D⁵, D⁶, J⁵, and J⁶ are independently selected from the groupconsisting of C, N, O, S and a covalent bond with the provisos that nomore than one is a covalent bond, K² is C, no more than one of D⁵, D⁶,J⁵, and J⁶ is O, no more than one of D⁵, D⁶, J⁵, and J⁶ is S, one of D⁵,D⁶, J⁵, and J⁶ must be a covalent bond when two of D⁵, D⁶, J⁵, and J⁶are O and S, and no more than four of D⁵, D⁶, J⁵, and J⁶ are N, with theprovisos that R¹⁶, R¹⁷, R¹⁸, and R¹⁹ are each independently selected tomaintain the tetravalent nature of carbon, trivalent nature of nitrogen,the divalent nature of sulfur, and the divalent nature of oxygen;

R¹⁶, R¹⁷, R¹⁸, and R¹⁹ are independently selected from the groupconsisting of hydrido, amidino, guanidino, carboxy, haloalkylthio,alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl,alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl,haloalkoxy, hydroxyalkyl, alkylenylamino, and cyano;

R¹⁶ and R¹⁹ are optionally Q^(b) with the proviso that no more than oneof R¹⁶ and R¹⁹ is Q^(b) at the same time and that Q^(b) is Q^(be);

Q^(b) is selected from the group consisting of NR²⁰R²¹, Q^(be) whereinQ^(be) is hydrido, C(NR²⁵)NR²³R²⁴, and N(R²⁶)C(NR²⁵)N(R²³)(R²⁴), withthe provisos that no more than one of R²⁰ and R²¹ is hydroxy at the sametime and that no more than one of R²³ and R²⁴ is hydroxy at the sametime;

R²⁰, R²¹, R²³, R²⁴, R²⁵, and R²⁶ are independently selected from thegroup consisting of hydrido, alkyl, and hydroxy;

Q^(s) is selected from the group consisting of a single covalent bond,CH₂, and CH₂CH₂.

In still another even more preferred embodiment of compounds of FormulaI or a pharmaceutically acceptable salt thereof,

J is O;

B is selected from the group consisting of C3-C7 cycloalkyl andC4-heterocyclyl, wherein each ring carbon may be optionally substitutedwith R³³, a ring carbon other than the ring carbon at the point ofattachment of B to A may be optionally substituted with oxo providedthat no more than one ring carbon is substituted by oxo at the sametime, ring carbons and a nitrogen adjacent to the carbon at the point ofattachment may be optionally substituted with R¹⁹ or R¹³, a ring carbonor nitrogen adjacent to the R⁹ position and two atoms from the point ofattachment may be substituted with R¹⁰, a ring carbon or nitrogenadjacent to the R¹³ position and two atoms from the point of attachmentmay be substituted with R¹², a ring carbon three atoms from the point ofattachment and adjacent to the R¹⁰ position may be substituted with R¹¹,a ring carbon three atoms from the point of attachment and adjacent tothe R¹² position may be substituted with R³³, and a ring carbon fouratoms from the point of attachment and adjacent to the R¹¹ and R³³positions may be substituted with R³⁴;

R⁹, R¹¹, and R¹³ are independently selected from the group consisting ofhydrido, hydroxy, amino, amidino, guanidino, lower alkylamino,alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl,amidosulfonyl, monoalkyl amidosulfonyl, alkyl, alkoxy, halo, haloalkyl,haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano;

R¹⁰ and R¹² are independently selected from the group consisting ofhydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy,hydroxy, amino, alkoxyamino, lower alkylamino, alkylsulfonamido,amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl,hydroxyalkyl, alkylenylamino, carboalkoxy, carboxy, carboxyalkyl,amidocarbonyl, halo, haloalkyl, and cyano;

R³³ and R³⁴ are independently selected from the group consisting ofhydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy,amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl,monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl,haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, andQ^(b);

A is selected from the group consisting of single covalent bond and(CH(R¹⁵))_(pa)—(W⁷)_(rr) wherein rr is an integer selected from 0through 1, pa is an integer selected from 0 through 3, and W⁷ isselected from the group consisting of (R⁷)NC(O) and N(R⁷);

R⁷ is selected from the group consisting of hydrido, hydroxy and alkyl;

R¹⁵ is selected from the group consisting of hydrido, halo, alkyl, andhaloalkyl;

Ψ is NH;

M is selected from the group consisting of N and R¹—C;

R¹ is selected from the group consisting of hydrido, hydroxy,hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl,alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy,and halo;

R² is Z⁰—Q;

Z⁰ is selected from the group consisting of covalent single bond, O, S,NH, and CH₂;

Q is selected from the group consisting of aryl and heteroaryl wherein acarbon adjacent to the carbon at the point of attachment is optionallysubstituted by R⁹, the other carbon adjacent to the carbon at the pointof attachment is optionally substituted by R¹³, a carbon adjacent to R⁹and two atoms from the carbon at the point of attachment is optionallysubstituted by R¹⁰, a carbon adjacent to R¹³ and two atoms from thecarbon at the point of attachment is optionally substituted by R¹², andany carbon adjacent to both R¹⁰ and R¹² is optionally substituted byR¹¹;

K is CH₂;

E⁰ is C(O)N(H);

Y⁰ is formula (IV):

 wherein D⁵, D⁶, J⁵, and J⁶ are independently selected from the groupconsisting of C, N, O, S and a covalent bond with the provisos that nomore than one is a covalent bond, K² is C, no more than one of D⁵, D⁶,J⁵, and J⁶ is O, no more than one of D⁵, D⁶, J⁵, and J⁶ is S, one of D⁵,D⁶, J⁵, and J⁶ must be a covalent bond when two of D⁵, D⁶, J⁵, and J⁶are O and S, and no more than four of D⁵, D⁶, J⁵ and J⁶ are N, with theprovisos that R¹⁶, R¹⁷, R¹⁸, and R¹⁹ are each independently selected tomaintain the tetravalent nature of carbon, trivalent nature of nitrogen,the divalent nature of sulfur, and the divalent nature of oxygen;

R¹⁶, R¹⁷, R¹⁸, and R¹⁹ are independently selected from the groupconsisting of hydrido, amidino, guanidino, carboxy, haloalkylthio,alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl,alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl,haloalkoxy, hydroxyalkyl, alkylenylamino, and cyano;

R¹⁶ and R¹⁹ are optionally Q^(b) with the proviso that no more than oneof R¹⁶ and R¹⁹ is Q^(b) at the same time and that Q^(b) is Q^(be);

Q^(b) is selected from the group consisting of NR²⁰R²¹, Q^(be) whereinQ^(be) is hydrido, and C(NR²⁵)NR²³R²⁴, with the provisos that no morethan one of R²⁰ and R²¹ is hydroxy at the same time and that no morethan one of R²³ and R²⁴ is hydroxy at the same time;

R²⁰, R²¹, R²³, R²⁴, and R²⁵ are independently selected from the groupconsisting of hydrido, alkyl, and hydroxy;

Q^(b) is selected from the group consisting of a single covalent bond,CH₂, and CH₂CH₂.

In a most preferred embodiment of compounds of Formula I or apharmaceutically acceptable salt thereof,

J is O;

B is the Formula:

R³², R³³, R³⁴, R³⁵, and R³⁶ are independently selected from the groupconsisting of hydrido, acetamido, haloacetamido, amidino, guanidino,alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio,amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl,halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy,carboxamido, cyano, and Q^(b);

A is selected from the group consisting of single covalent bond and(CH(R¹⁵))_(pa)—(W⁷)_(rr) wherein rr is an integer selected from 0through 1, pa is an integer selected from 0 through 3, and W⁷ is N(R⁷);

R⁷ is selected from the group consisting of hydrido and alkyl;

R¹⁵ is selected from the group consisting of hydrido, halo, alkyl; andhaloalkyl;

Ψ is NH;

M is selected from the group consisting of N and R¹—C;

R¹ is selected from the group consisting of hydrido, hydroxy,hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl,alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy,and halo;

R² is Z⁰—Q;

Z⁰ is a covalent single bond;

Q is selected from the group consisting of aryl and heteroaryl wherein acarbon adjacent to the carbon at the point of attachment is optionallysubstituted by R⁹, the other carbon adjacent to the carbon at the pointof attachment is optionally substituted by R¹³, a carbon adjacent to R⁹and two atoms from the carbon at the point of attachment is optionallysubstituted by R¹⁰, a carbon adjacent to R¹³ and two atoms from thecarbon at the point of attachment is optionally substituted by R¹², andany carbon adjacent to both R¹⁰ and R¹² is optionally substituted byR¹¹;

R⁹, R¹¹, and R¹³ are independently selected from the group consisting ofhydrido, hydroxy, amino, amidino, guanidino, lower alkylamino,alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl,monoalkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy,hydroxyalkyl, carboxy, carboxamido, and cyano;

R¹⁰ and R¹² are independently selected from the group consisting ofhydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy,alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino,alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl 10amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl, carboalkoxy,carboxy, carboxyalkyl, carboxyamido, and cyano;

K is CH₂;

E⁰ is C(O)N(H);

Y⁰ is formula (IV):

 wherein D⁵, D⁶, J⁵, and J⁶ are independently selected from the groupconsisting of C, N, O, S and a covalent bond with the provisos that nomore than one is a covalent bond, K² is C, no more than one of D⁵, D⁶,J⁵, and J⁶ is O, no more than one of D⁵, D⁶, J⁵, and J⁶ is S, one of D⁵,D⁶, J⁵, and J⁶ must be a covalent bond when two of D⁵, D⁶, J⁵, and J⁶are O and S, and no more than four of D⁵, D⁶, J⁵, and J⁶ are N;

R¹⁶, R¹⁷, R¹⁸, and R¹⁹ are independently selected from the groupconsisting of hydrido, amidino, guanidino, carboxy, haloalkylthio,alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl,alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl,haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;

R¹⁶ and R¹⁹ are optionally Q^(b) with the proviso that no more than oneof ^(16R) and R¹⁹ is Q^(b) at the same time and that Q^(b) is Q^(be);

Q^(b) is selected from the group consisting of NR²⁰R²¹, Q^(be) whereinQ^(be) is hydrido, and C(NR²⁵ 23)NRR²⁴;

R²⁰, R²¹, R²³, R²⁴, and R²⁵ are independently selected from the groupconsisting of hydrido and alkyl;

Q^(s) is CH₂.

In another most preferred embodiment of compounds of Formula I or apharmaceutically acceptable salt thereof,

J is O;

B is optionally selected from the group consisting of hydrido, C2-C8alkyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein eachmember of group B is optionally substituted at any carbon up to andincluding 6 atoms from the point of attachment of B to A with one ormore of the group consisting of R³², R³³, R³⁴, R³⁵ and R³⁶;

R³², R³³, R³⁴, R³⁵, and R³⁶ are independently selected from the groupconsisting of hydrido, acetamido, haloacetamido, amidino, guanidino,alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio,amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl,halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy,carboxamido, cyano, and Q^(b);

A is selected from the group consisting of single covalent bond and(CH(R¹⁵))_(pa)—(W⁷)_(rr) wherein rr is an integer selected from 0through 1, pa is an integer selected from 0 through 3, and W⁷ is N(R⁷);

R⁷ is selected from the group consisting of hydrido and alkyl;

R¹⁵ is selected from the group consisting of hydrido, halo, alkyl, andhaloalkyl;

Ψ is NH;

M is selected from the group consisting of N and R¹—C;

R¹ is selected from the group consisting of hydrido, hydroxy,hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl,alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy,and halo;

R² is Z⁰—Q;

Z⁰ is a covalent single bond;

Q is selected from the group consisting of aryl and heteroaryl wherein acarbon adjacent to the carbon at the point of attachment is optionallysubstituted by R⁹, the other carbon adjacent to the carbon at the pointof attachment is optionally substituted by R¹³, a carbon adjacent to R⁹and two atoms from the carbon at the point of attachment is optionallysubstituted by R¹⁰, a carbon adjacent to R¹³ and two atoms from thecarbon at the point of attachment is optionally substituted by R¹², andany carbon adjacent to both R¹⁰ and R¹² is optionally substituted byR¹¹;

R⁹, R¹¹, and R¹³ are independently selected from the group consisting ofhydrido, hydroxy, amino, amidino, guanidino, lower alkylamino,alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl,monoalkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy,hydroxyalkyl, carboxy, carboxamido, and cyano;

R¹⁰ and R¹² are independently selected from the group consisting ofhydrido, acetamido, haloacetamido, aridino, guanidino, alkyl, alkoxy,alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino,alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkylamidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl, carboalkoxy,carboxy, carboxyalkyl, carboxyamido, and cyano;

K is CH₂;

E⁰ is C(O)N(H);

Y⁰ is formula (IV):

 wherein D⁵, D⁶, J⁵, and J⁶ are independently selected from the groupconsisting of C, N, O, S and a covalent bond with the provisos that nomore than one is a covalent bond, K² is C, no more than one of D⁵, D⁶,J⁵, and J⁶ is O, no more than one of D⁵, D⁶, J⁵, and J⁶ is S, one of D⁵,D⁶, J⁵, and J⁶ must be a covalent bond when two of D⁵, D⁶, J⁵, and J⁶are O and S, and no more than four of D⁵, D⁶, J⁵, and J⁶ are N, with theprovisos that R¹⁶, R¹⁷, R¹⁸, and R¹⁹ are each independently selected tomaintain the tetravalent nature of carbon, trivalent nature of nitrogen,the divalent nature of sulfur, and the divalent nature of oxygen;

R¹⁶, R¹⁷, R¹⁸, and R¹⁹ are independently selected from the groupconsisting of hydrido, amidino, guanidino, carboxy, haloalkylthio,alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl,alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl,haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;

R¹⁶ and R¹⁹ are optionally Q^(b) with the proviso that no more than oneof R¹⁶ and R¹⁹ is Q^(b) at the same time and that Q^(b) is Q^(be);

Q^(b) is selected from the group consisting of NR²⁰R²¹, Q^(be) whereinQ^(be) is hydrido, N(R²⁶)C(NR²⁵)N(R²³)(R²⁴), and C(NR²⁵)NR²³R²⁴ ^(;)

R²⁰, R²¹, R²³, R²⁴, R²⁵, and R²⁶ are independently selected from thegroup consisting of hydrido and alkyl;

Q^(s) is CH₂.

In still another most preferred embodiment of compounds of Formula I ora pharmaceutically acceptable salt thereof,

J is O;

B is selected from the group consisting of C3-C7 cycloalkyl andC4-heterocyclyl, wherein each ring carbon may be optionally substitutedwith R³³, a ring carbon other than the ring carbon at the point ofattachment of B to A may be optionally substituted with oxo providedthat no more than one ring carbon is substituted by oxo at the sametime, ring carbons and nitrogens adjacent to the carbon at the point ofattachment may be optionally substituted with R⁹ or R¹³, a ring carbonor nitrogen adjacent to the R⁹ position and two atoms from the point ofattachment may be substituted with R¹⁰, a ring carbon or nitrogenadjacent to the R¹³ position and two atoms from the point of attachmentmay be substituted with R¹², a ring carbon three atoms from the point ofattachment and adjacent to the R¹⁰ position may be substituted with R¹¹,a ring carbon three atoms from the point of attachment and adjacent tothe R¹² position may be substituted with R³³, and a ring carbon fouratoms from the point of attachment and adjacent to the R¹¹ and R³³positions may be substituted with R³⁴;

R⁹, R¹¹, and R¹³ are independently selected from the group consisting ofhydrido, hydroxy, amino, amidino, guanidino, lower alkylamino,alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl,monoalkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy,hydroxyalkyl, carboxy, carboxamido, and cyano;

R¹⁰ and R¹² are independently selected from the group consisting ofhydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy,alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino,alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkylamidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl, carboalkoxy,carboxy, carboxyalkyl, carboxyamido, and cyano;

R³³ and R³⁴ are independently selected from the group consisting ofhydrido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, loweralkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkylamidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl,carboalkoxy, carboxy, carboxamido, and cyano;

R³³ is optionally Q^(b);

A is selected from the group consisting of single covalent bond and(CH(R¹⁵))_(pa)—(W⁷)_(rr) wherein rr is an integer selected from 0through 1, pa is an integer selected from 0 through 3, and W⁷ is N(R⁷);

R⁷ is selected from the group consisting of hydrido, hydroxy and alkyl;

R¹⁵ is selected from the group consisting of hydrido, halo, alkyl, andhaloalkyl;

Ψ is NH;

M is selected from the group consisting of N and R¹—C;

R¹ is selected from the group consisting of hydrido, hydroxy,hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl,alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy,and halo;

R² is Z⁰—Q;

Z⁰ is a covalent single bond;

Q is selected from the group consisting of aryl and heteroaryl wherein acarbon adjacent to the carbon at the point of attachment is optionallysubstituted by R⁹, the other carbon adjacent to the carbon at the pointof attachment is optionally substituted by R¹³, a carbon adjacent to R⁹and two atoms from the carbon at the point of attachment is optionallysubstituted by R¹⁰, a carbon adjacent to R¹³ and two atoms from thecarbon at the point of attachment is optionally substituted by R¹², andany carbon adjacent to both R¹⁰ and R¹² is optionally substituted byR¹¹;

K is CH₂;

E⁰ is C(O)N(H);

Y⁰ is formula (IV):

 wherein D⁵, D⁶, J⁵, and J⁶ are independently selected from the groupconsisting of C, N, O, S and a covalent bond with the provisos that nomore than one is a covalent bond, K² is C, no more than one of D⁵, D⁶,J⁵, and J⁶ is O, no more than one of D⁵, D⁶, J⁵, and J⁶ is S, one of D⁵,D⁶, J⁵, and J⁶ must be a covalent bond when two of D⁵, D⁶, J⁵, and J⁶are O and S, and no more than four of D⁵, D⁶, J⁵, and J⁶ are N, with theprovisos that R¹⁶, R¹⁷, R¹⁸, and R¹⁹ are each independently selected tomaintain the tetravalent nature of carbon, trivalent nature of nitrogen,the divalent nature of sulfur, and the divalent nature of oxygen;

R¹⁶, R¹⁷, R¹⁸, and R¹⁹ are independently selected from the groupconsisting of hydrido, amidino, guanidino, carboxy, haloalkylthio,alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl,alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl,haloalkoxy, hydroxyalkyl, alkylenylamino, and cyano;

R¹⁶ and R¹⁹ are optionally Q^(b) with the proviso that no more than oneof R¹⁶ and R¹⁹ is Q^(b) at the same time and that Q^(b) is Q^(be);

Q^(b) is selected from the group consisting of NR²⁰R²¹, Q^(be) whereinQ^(be) is hydrido, and C(NR²⁵)NR²³R²⁴;

R²⁰, R²¹, R²³, R²⁴, and R²⁵ are independently selected from the groupconsisting of hydrido and alkyl;

Q^(s) is CH₂.

In a preferred specific embodiment of Formula I, compounds have theFormula I-S:

or a pharmaceutically acceptable salt thereof, wherein;

B is the Formula:

R³², R³³, R³⁴, R³⁵, and R³⁶ are independently selected from the groupconsisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl,isopropyl, propyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino,methoxyaminno, ethoxyamino, acetamido, trifluoroacetamido, nitro,aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino,N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio,trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl,2,2,3,3,3-pentafluoropropyl, trifluoromethoxy,1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl,N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, acetyl, propanoyl,trifluoroacetyl, pentafluoropropanoyl, hydroxymethyl, 1-hydroxyethyl,2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl,2,2,2-trifluoro-1-trifluoromethyl-1-hydroxyethyl, carboxymethyl,methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl,N,N-dimethylamidocarbonyl, cyano, and Q^(b);

B is selected from the group consisting of hydrido, trimethylsilyl,ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butenyl,3-butenyl, 2-butynyl, sec-butyl, tert-butyl, isobutyl, 2-methylpropenyl,1-pentyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-pentynyl, 3-pentynyl,2-pentyl, 1-methyl-2-butenyl, 1-methyl-3-butenyl, 1-methyl-2-butynyl,3-pentyl, 1-ethyl-2-propenyl, 2-methylbutyl, 2-methyl-2-butenyl,2-methyl-3-butenyl, 2-methyl-3-butynyl, 3-methylbutyl,3-methyl-2-butenyl, 3-methyl-3-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl,4-hexenyl, 5-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl,1-methyl-2-pentenyl, 1-methyl-3-pentenyl, 1-methyl-4-pentenyl,1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 3-hexyl, 1-ethyl-2-butenyl,1-ethyl-3-butenyl, 1-propyl-2-propenyl, 1-ethyl-2-butynyl, 1-heptyl,2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 2-heptynyl,3-heptynyl, 4-heptynyl, 5-heptynyl, 2-heptyl, 1-methyl-2-hexenyl,1-methyl-3-hexenyl, 1-methyl-4-hexenyl, 1-methyl-5-hexenyl,1-methyl-2-hexynyl, 1-methyl-3-hexynyl, 1-methyl-4-hexynyl, 3-heptyl,1-ethyl-2-pentenyl, 1-ethyl-3-pentenyl, 1-ethyl-4-pentenyl,1-butyl-2-propenyl, 1-ethyl-2-pentynyl, 1-ethyl-3-pentynyl, 1-octyl,2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl,2-octynyl, 3-octynyl, 4-octynyl, 5-octynyl, 6-octynyl, 2-octyl,1-methyl-2-heptenyl, 1-methyl-3-heptenyl, 1-methyl-4-heptenyl,1-methyl-5-heptenyl, 1-methyl-6-heptenyl, 1-methyl-2-heptynyl,1-methyl-3-heptynyl, 1-methyl-4-heptenyl, 1-methyl-5-heptenyl,1-methyl-6-heptenyl, 1-methyl-2-heptenyl, 1-methyl-3-heptynyl,1-methyl-4-heptynyl, 1-methyl-5-heptynyl, 3-octyl, 1-ethyl-2-hexenyl,1-ethyl-3-hexenyl, 1-ethyl-4-hexenyl, 1-ethyl-2-hexynyl,1-ethyl-3-hexynyl, 1-ethyl-4-hexynyl, 1-ethyl-5-hexenyl,1-pentyl-2-propenyl, 4-octyl, 1-propyl-2-pentenyl, 1-propyl-3-pentenyl,1-propyl-4-pentenyl, 1-butyl-2-butenyl, 1-propyl-2-pentynyl,1-propyl-3-pentynyl, 1-butyl-2-butynyl, 1-butyl-3-butenyl,2,2,2-trifluoroethyl, 2,2-difluoropropyl,4-trifluoromethyl-5,5,5-trifluoropentyl, 4-trifluoromethylpentyl,5,5,6,6,6-pentafluorohexyl, and 3,3,3-trifluoropropyl, wherein eachmember of group B is optionally substituted at any carbon up to andincluding 5 atoms from the point of attachment of B to A with one ormore of the group consisting of R³², R³³, R³⁴, R³⁵ and R³⁶;

B is optionally selected from the group consisting of cyclopropyl,cyclobutyl, oxetan-2-yl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl,azetidin-3-yl, thiaetan-2-yl, thiaetan-3-yl, cyclopentyl, cyclohexyl,adamantyl, norbornyl, 3-trifluoromethylnorbornyl,bicyclo[3.1.0]hexan-6-yl, cycloheptyl, and cyclooctyl, wherein each ringcarbon is optionally substituted with R³³, ring carbons or a nitrogenadjacent to the carbon atom at the point of attachment is optionallysubstituted with R⁹ or R¹³, a ring carbon or a nitrogen adjacent to theR⁹ position and two atoms from the point of attachment is optionallysubstituted with R¹⁰, and a ring carbon or a nitrogen adjacent to theR¹³ position and two atoms from the point of attachment is optionallysubstituted with R¹²;

R⁹, R¹⁰, R¹¹, R¹², and R¹³ are independently selected from the groupconsisting of hydrido, amidino, guanidino, carboxy, carboxymethyl,methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, isopropoxy, propoxy,hydroxy, amino, methoxyamino, ethoxyamino, acetamido,trifluoroacetamido, nitro, aminomethyl, 1-aminoethyl, 2-aminoethyl,N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio,isopropylthio, trifluoromethylthio, trifluoromethyl, pentafluoroethyl,2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy,1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, methanesulfonamido,amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, acetyl,propanoyl, trifluoroacetyl, pentafluoropropanoyl, hydroxymethyl,1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl,2,2,2-trifluoro-1-trifluoromethyl-1-hydroxyethyl, carboxymethyl,methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl,N,N-dimethylamidocarbonyl, and cyano;

A is selected from the group consisting of single covalent bond, O, S,NH, N(CH₃), N(OH), C(O), CH₂, CH₃CH, CF₃CH, NHC(O), N(CH₃)C(O), C(O)NH,C(O)N(CH₃), CF₃CC(O), C(O)CCH₃, C(O)CCF₃, CH₂C(O), (O)CCH₂, CH₂CH₂,CH₂CH₂CH₂, CH₃CHCH₂, CF₃CHCH₂, CH₃CC(O)CH₂, CF₃CC(O)CH₂, CH₂C(O)CCH₃,CH₂C(O)CCF₃, CH₂CH₂C(O), and CH₂(O)CCH₂;

A is optionally selected from the group consisting of CH₂N(CH₃),CH₂N(CH₂CH₃), CH₂CH₂N(CH₃), and CH₂CH₂N(CH₂CH₃) with the proviso that Bis hydrido;

M is selected from the group consisting of N and R¹—C;

R¹ is selected from the group consisting of hydrido, hydroxy, amino,thiol, amidino, hydroxyamino, aminomethyl, 1-aminoethyl, 2-aminoethyl,methylamino, dimethylamino, cyano, methyl, ethyl, isopropyl, propyl,trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl,2,2,3,3,3-pentafluoropropyl, methoxy, ethoxy, propoxy, hydroxymethyl,1-hydroxyethyl, 2-hydroxyethyl, methoxyamino, ethoxyamino, methylthio,ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro,and bromo;

R² is Z⁰—Q;

Z⁰ is selected from the group consisting of covalent single bond, O, S,NH, CH₂, CH₂CH₂, CH(OH), CH(NH₂), CH₂CH(OH), CH₂CHNH₂, CH(OH)CH₂, andCH(NH₂)CH₂;

Q is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl,2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl,3-pyrazolyl, 4-pyrazolyl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl,1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-3-yl,1,3,4-oxadiazol-5-yl, 3-isothiazolyl, 5-isothiazolyl, 2-oxazolyl,2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl,3-pyridazinyl, 4-pyridazinyl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl,1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, 1,2,3-triazin-4-yl, and1,2,3-triazin-5-yl, wherein a carbon adjacent to the carbon at the pointof attachment is optionally substituted by R⁹, the other carbon adjacentto the carbon at the point of attachment is optionally substituted byR¹³, a carbon adjacent to R⁹ and two atoms from the carbon at the pointof attachment is optionally substituted by R¹⁰, a carbon adjacent to R¹³and two atoms from the carbon at the point of attachment is optionallysubstituted by R¹², and any carbon adjacent to both R¹⁰ and R¹² isoptionally substituted by R¹¹;

K is CHR^(4a) wherein R^(4a) is selected from the group consisting ofmethyl, ethyl, propyl, isopropyl, hydroxymethyl, 1-hydroxyethyl,methoxymethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoromethyl,methylthiomethyl, and hydrido;

E⁰ is a covalent single bond, C(O)N(H), (H)NC(O), and S(O)₂N(H);

Y⁰ is selected from the group of formulas consisting of:

R¹⁶, R¹⁷, R¹⁸, and R¹⁹ are independently selected from the groupconsisting of hydrido, methyl, ethyl, isopropyl, propyl, amidino,guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy,amino, methoxyamino, ethoxyamino, aminomethyl, 1-aminoethyl,2-aminoethyl, N-N-methylamino, dimethylamino, N-ethylamino, methylthio,ethylthio, isopropylthio, trifluoromethylthio, methylsulfinyl,ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl,pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl,trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo,amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, acetyl,propanoyl, trifluoroacetyl, pentafluoropropanoyl, hydroxymethyl,1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, andcyano;

R¹⁶ and R¹⁹ are optionally Q^(b) with the proviso that no more than oneof R¹⁶ and R¹⁹ is Q^(b) at the same time and that Q^(b) is Q^(be);

Q^(b) is selected from the group consisting of NR²⁰R²¹, Q^(be) whereinQ^(be) is hydrido, C(NR²⁵)NR²³R²⁴ and N(R²⁶)C(NR²⁵)N(R²³)(R²⁴), with theproviso that no more than one of R²⁰ and R²¹ is hydroxy, N-methylamino,and N,N-dimethylamino at the same time and that no more than one of R²³and R²⁴ is hydroxy, N-methylamino, and N,N-dimethylamino at the sametime;

R²⁰, R²¹, R²³, R²⁴, R²⁵, and R²⁶ are independently selected from thegroup consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl,hydroxy, 2-aminoethyl, 2-(N-methylamino)ethyl, and2-(N,N-dimethylamino)ethyl;

Q^(s) is selected from the group consisting of a single covalent bond,CH₂, CH₂CH₂, CH₃CH, CF₃CH, CH₃CHCH₂, CF₃CHCH₂, CH₂(CH₃)CH, CH═CH, CF═CH,C(CH₃)═CH, CH═CHCH₂, CF═CHCH₂, C(CH₃)═CHCH₂, CH₂CH═CH, CH₂CF═CH,CH₂C(CH₃)═CH, CH₂CH═CHCH₂, CH₂CF═CHCH₂, CH₂C(CH₃)═CHCH₂, CH₂CH═CHCH₂CH₂,CH₂CF═CHCH₂CH₂, and CH₂C(CH₃)═CHCH₂CH₂.

In a more preferred specific embodiment of Formula I, compounds have theFormula I-MPS wherein B is an aromatic:

(I-MPS wherein B is aromatic)

or a pharmaceutically acceptable salt thereof, wherein;

B is the Formula:

R³², R³³, R³⁴, R³⁵, and R³⁶ are independently selected from the groupconsisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy,isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino,acetamido, trifluoroacetamido, N-methylamino, dimethylamino,N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl,pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl,trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo,amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl,hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl,2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl,amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano,and Q^(b);

A is selected from the group consisting of single covalent bond, NH,N(CH₃), N(OH), CH₂, CH₃CH, CF₃CH, NHC(O), N(CH₃)C(O), C(O)NH,C(O)N(CH₃), CH₂CH₂, CH₂CH₂CH₂, CH₃CHCH₂, and CF₃CHCH₂;

Q^(b) is selected from the group consisting of NR²⁰R²¹, Q^(be) whereinQ^(be) is hydrido, and C(NR²⁵)NR²³R²⁴, with the provisos that no morethan one of R²⁰ and R²¹ is hydroxy at the same time and that no morethan one of R²³ and R²⁴ is hydroxy at the same time;

R²⁰, R²¹, R²³, R²⁴, and R²⁵ are independently selected from the groupconsisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, andhydroxy;

Q^(s) is selected from the group consisting of a single covalent bond,CH₂, and CH₂CH₂.

In another more preferred specific embodiment of Formula I, compoundshave the Formula I-MPS wherein B is a non-cyclic substituent:

(I-MPS wherein B is a non-cyclic substituent)

or a pharmaceutically acceptable salt thereof, wherein;

B is selected from the group consisting of hydrido, ethyl, 2-propenyl,2-propynyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl, 2-butynyl,sec-butyl, tert-butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 2-pentynyl, 3-pentynyl, 2-pentyl,1-methyl-2-butenyl, 1-methyl-3-butenyl, 1-methyl-2-butynyl, 3-pentyl,1-ethyl-2-propenyl, 2-methylbutyl, 2-methyl-2-butenyl,2-methyl-3-butenyl, 2-methyl-3-butynyl, 3-methylbutyl,3-methyl-2-butenyl, 3-methyl-3-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl,4-hexenyl, 5-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl,1-methyl-2-pentenyl, 1-methyl-3-pentenyl, 1-methyl-4-pentenyl,1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 3-hexyl, 1-ethyl-2-butenyl,1-ethyl-3-butenyl, 1-propyl-2-propenyl, 1-ethyl-2-butynyl, 1-heptyl,2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 2-heptynyl,3-heptynyl, 4-heptynyl, 5-heptynyl, 2-heptyl, 1-methyl-2-hexenyl,1-methyl-3-hexenyl, 1-methyl-4-hexenyl, 1-methyl-5-hexenyl,1-methyl-2-hexynyl, 1-methyl-3-hexynyl, 1-methyl-4-hexynyl, 3-heptyl,1-ethyl-2-pentenyl, 1-ethyl-3-pentenyl, 1-ethyl-4-pentenyl,1-butyl-2-propenyl, 1-ethyl-2-pentynyl, 1-ethyl-3-pentynyl,2,2,2-trifluoroethyl, 2,2-difluoropropyl,4-trifluoromethyl-5,5,5-trifluoropentyl, 4-trifluoromethylpentyl,5,5,6,6,6-pentafluorohexyl, and 3,3,3-trifluoropropyl, wherein eachmember of group B is optionally substituted at any carbon up to andincluding 5 atoms from the point of attachment of B to A with one ormore of the group consisting of R³², R³³, R³⁴, R³⁵, and R³⁶;

R³², R³³, R³⁴, R³⁵, and R³⁶ are independently selected from the groupconsisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy,isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino,acetamido, trifluoroacetamido, N-methylamnino, dimethylamino,N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl,pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl,trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo,amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl,hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl,2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl,amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano,and Q^(b);

A is selected from the group consisting of single covalent bond, NH,N(CH₃), N(OH), CH₂, CH₃CH, CF₃CH, NHC(O), N(CH₃)C(O), C(O)NH,C(O)N(CH₃), CH₂CH₂, CH₂CH₂CH₂, CH₃CHCH₂, and CF₃CHCH₂;

A is optionally selected from the group consisting of CH₂N(CH₃),CH₂N(CH₂CH₃), CH₂CH₂N(CH₃), and CH₂CH₂N(CH₂CH₃) with the proviso that Bis hydrido;

Q^(b) is selected from the group consisting of NR²⁰R²¹, Q^(be), whereinQ^(be) is hydrido, C(NR²⁵)NR²³R²⁴, and N(R²⁶)C(NR²⁵)N(R²³)(R²⁴), withthe provisos that no more than one of R²⁰ and R²¹ is hydroxy at the sametime and that no more than one of R²³ and R²⁴ is hydroxy at the sametime;

R²⁰, R²¹, R²³, R²⁴, R²⁵, and R²⁶ are independently selected from thegroup consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl,and hydroxy;

Q^(s) is selected from the group consisting of a single covalent bond,CH₂, and CH₂CH₂.

In still another more preferred specific embodiment of Formula I,compounds have the Formula I-MPS wherein B is a non-aromatic cyclicsubstituent:

(I-MPS wherein B is a non-aromatic cyclic substituent)

or a pharmaceutically acceptable salt thereof, wherein;

B is optionally selected from the group consisting of cyclopropyl,cyclobutyl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl,thiaetan-3-yl, cyclopentyl, cyclohexyl, norbornyl,bicyclo[3.1.0]hexan-6-yl, and cycloheptyl , wherein each ring carbon isoptionally substituted with R³³, ring carbons or a nitrogen adjacent tothe carbon atom at the point of attachment is optionally substitutedwith R⁹ or R¹³, a ring carbon or nitrogen adjacent to the R⁹ positionand two atoms from the point of attachment is optionally substitutedwith R¹⁰, and a ring carbon or nitrogen adjacent to the R¹³ position andtwo atoms from the point of attachment is optionally substituted withR¹²;

A is selected from the group consisting of single covalent bond, NH,N(CH₃), N(OH), CH₂, CH₃CH, CF₃CH, NHC(O), N(CH₃)C(O), C(O)NH,C(O)N(CH₃), CH₂CH₂, CH₂CH₂CH₂, CH₃CHCH₂, and CF₃CHCH₂;

R³³ are independently selected from the group consisting of hydrido,amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy,hydroxy, amino, methoxyamino, ethoxyamino, acetamido,trifluoroacetamido, N-methylamino, dimethylamino, N-ethylamino,methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl,2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy,1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl,N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl,1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl,methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl,N,N-dimethylamidocarbonyl, cyano, and Q^(b);

Q^(b) is selected from the group consisting of NR²⁰R²¹, Q^(be) whereinQ^(be) is hydrido, and C(NR²⁵)NR²³R²⁴, with the provisos that no morethan one of R²⁰ and R²¹ is hydroxy at the same time and that no morethan one of R²³ and R²⁴ is hydroxy at the same time;

R²⁰, R²¹, R²³, R²⁴, and R²⁵ are independently selected from the groupconsisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, andhydroxy;

Q^(s) is selected from the group consisting of a single covalent bond,CH₂, and CH₂CH₂.

The more preferred specific embodiment (I-MPS) compounds of the presentinvention having the Formula:

or a pharmaceutically acceptable salt thereof, have common structuralunits, wherein;

M is selected from the group consisting of N and R¹—C;

R¹ is selected from the group consisting of hydrido, hydroxy, amino,amidino, hydroxyamino, aminomethyl, 1-aminoethyl, methylamino,dimethylamino, cyano, methyl, ethyl, trifluoromethyl, pentafluoroethyl,2,2,2-trifluoroethyl, methoxy, hydroxymethyl, 1-hydroxyethyl,2-hydroxyethyl, methoxyamino, methylthio, ethylthio, trifluoromethoxy,1,1,2,2-tetrafluoroethoxy, fluoro, chloro, and bromo;

R² is Z⁰—Q;

Z⁰ is selected from the group consisting of covalent single bond, O, S,NH, and CH₂;

Q is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl,2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl,3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and1,3,5-triazin-2-yl, wherein a carbon adjacent to the carbon at the pointof attachment is optionally substituted by R⁹ the other carbon adjacentto the carbon at the point of attachment is optionally substituted byR¹³, a carbon adjacent to R⁹ and two atoms from the carbon at the pointof attachment is optionally substituted by R¹⁰, a carbon adjacent to R¹³and two atoms from the carbon at the point of attachment is optionallysubstituted by R¹², and any carbon adjacent to both R¹⁰ and R¹² isoptionally substituted by R¹¹;

R⁹, R¹¹ and R¹³ are independently selected from the group consisting ofhydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl,methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino,N,N-dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio,trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl,2,2,3,3,3-pentafluoropropyl, trifluoromethoxy,1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, methanesulfonamido,amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl,hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl,2,2,2-trifluoro-1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl,N,N-dimethylamidocarbonyl, and cyano;

R¹⁰ and R¹² are independently selected from the group consisting ofhydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl,propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino,methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, aminomethyl,1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino,methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl,N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl,2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl,ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl,N,N-dimethylamidocarbonyl, fluoro, chloro, bromo, and cyano;

Y⁰ is selected from the group of formulas consisting of:

R¹⁶, R¹⁷, R¹⁸, and R¹⁹ are independently selected from the groupconsisting of hydrido, methyl, ethyl, isopropyl, propyl, carboxy,amidino, guanidino, methoxy, ethoxy, isopropoxy, propoxy, hydroxy,amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino,dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio,trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl,ethylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl,2,2,3,3,3-pentafluoropropyl, trifluoromethoxy,1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl,N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl,1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, andcyano;

R¹⁶ and R¹⁹ are optionally Q^(b) with the proviso that no more than oneof R¹⁶ and R¹⁹ is Q^(b) at the same time and that Q^(b) is Q^(be).

In a most preferred specific embodiment of Formula I, compounds have theFormula I-EMPS wherein B is an aromatic:

(I-EMPS wherein B is aromatic)

or a pharmaceutically acceptable salt thereof, wherein;

B is the Formula:

R³², R³³, R³⁴, R³⁵, and R³⁶ are independently selected from the groupconsisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy,ethoxy, hydroxy, amino, N-methylamino, dimethylamino, methylthio,ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl,fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl,hydroxymethyl, amidocarbonyl, carboxy, cyano, and Q^(b);

A is selected from the group consisting of single covalent bond, NH,N(CH₃), CH₂, CH₃CH, and CH₂CH₂;

Q^(b) is selected from the group consisting of NR²⁰R²¹ andC(NR²⁵)NR²³R²⁴, with the proviso that said Q^(b) group is bondeddirectly to a carbon atom;

R²⁰, R²¹, R²³, R²⁴ and R²⁵ are independently selected from the groupconsisting of hydrido, methyl, and ethyl;

Q^(s) is CH₂.

In another most preferred specific embodiment of Formula I, compoundshave the Formula I-EMPS wherein B is a non-cyclic substituent:

(I-EMPS wherein B is a non-cyclic substituent)

or a pharmaceutically acceptable salt thereof, wherein;

B is selected from the group consisting of hydrido, ethyl, 2-propenyl,2-propynyl, propyl, isopropyl, butyl, 2-butenyl, 2-butynyl, sec-butyl,tert-butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl,3-pentenyl, 2-pentynyl, 3-pentynyl, 2-pentyl, 3-pentyl, 2-methylbutyl,2-methyl-2-butenyl, 3-methylbutyl, 3-methyl-2-butenyl, 1-hexyl,2-hexenyl, 3-hexenyl, 4-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl,2-hexyl, 1-methyl-2-pentenyl, 1-methyl-3-pentenyl, 1-methyl-2-pentynyl,1-methyl-3-pentynyl, 3-hexyl, 1-ethyl-2-butenyl, 1-heptyl, 2-heptenyl,3-heptenyl, 4-heptenyl, 5-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl,5-heptynyl, 2-heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl,1-methyl-4-hexenyl, 1-methyl-2-hexynyl, 1-methyl-3-hexynyl,1-methyl-4-hexynyl, 3-heptyl, 1-ethyl-2-pentenyl, 1-ethyl-3-pentenyl,1-ethyl-2-pentynyl, 1-ethyl-3-pentynyl, 2,2,2-trifluoroethyl,2,2-difluoropropyl, 4-trifluoromethyl-5,5,5-trifluoropentyl,4-trifluoromethylpentyl, 5,5,6,6,6-pentafluorohexyl, and3,3,3-trifluoropropyl, wherein each member of group B is optionallysubstituted at any carbon up to and including 5 atoms from the R³²,point of attachment of B to A with one or more of the group consistingof R³², R³³, R³⁴, R³⁵, and R³⁶;

R³², R³³, R³⁴, R³⁵, and R³⁶ are independently selected from the groupconsisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy,ethoxy, hydroxy, amino, N-methylamino, dimethylamino, methylthio,ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl,fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl,hydroxymethyl, amidocarbonyl, carboxy, cyano, and Q^(b);

A is selected from the group consisting of single covalent bond, NH,N(CH₃), CH₂, CH₃CH, and CH₂CH₂;

A is optionally selected from the group consisting of CH₂N(CH₃),CH₂N(CH₂CH₃), CH₂CH₂N(CH₃), and CH₂CH₂N(CH₂CH₃) with the proviso that Bis hydrido;

Q^(b) is selected from the group consisting of NR²⁰R²¹, C(NR²⁵)NR²³R²⁴,and N(R²⁶)C(NR²⁵)N(R²³)(R²⁴), with the proviso that said Q^(b) group isbonded directly to a carbon atom;

R²⁰, R²¹, R²³, R²⁴, R²⁵, and R²⁶ are independently selected from thegroup consisting of hydrido, methyl, and ethyl;

Q^(s) is CH₂.

In still another most preferred specific embodiment of Formula I,compounds have the Formula I-EMPS wherein B is a non-aromatic cyclicsubstituent:

(I-EMPS wherein B is a non-aromatic cyclic substituent)

or a pharmaceutically acceptable salt thereof, wherein;

B is optionally selected from the group consisting of cyclopropyl,cyclobutyl, oxetan-3-yl, azetidin-3-yl, thiaetan-3-yl, cyclopentyl, andcyclohexyl, wherein each ring carbon is optionally substituted with R³³,ring carbons or a nitrogen adjacent to the carbon atom at the point ofattachment is optionally substituted with R⁹ or R¹³, a ring carbon ornitrogen adjacent to the R⁹ position and two atoms from the point ofattachment is optionally substituted with R¹⁰, and a ring carbon ornitrogen adjacent to the R¹³ position and two atoms from the point ofattachment is optionally substituted with R¹²;

R³³ are independently selected from the group consisting of hydrido,amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, carboxy,amino, N-methylamino, dimethylamino, methylthio, ethylthio,trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro,bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl,amidocarbonyl, cyano, and Q^(b);

A is selected from the group consisting of single covalent bond, NH,N(CH₃), CH₂, CH₃CH, and CH₂CH₂;

Q^(b) is selected from the group consisting of NR²⁰R²¹ andC(NR²⁵)NR²³R²⁴, with the proviso that said Q^(b) group is bondeddirectly to a carbon atom;

R²⁰, R²¹, R²³, R²⁴, and R²⁵ are independently selected from the groupconsisting of hydrido, methyl, and ethyl;

Q^(s) is CH₂.

The most preferred specific embodiment (I-EMPS) compounds of the presentinvention having the Formula:

or a pharmaceutically acceptable salt thereof, have common structuralunits, wherein;

M is selected from the group consisting of N and R¹—C;

R¹ is selected from the group consisting of hydrido, hydroxy, amino,amidino, hydroxyamino, aminomethyl, methylamino, cyano, methyl,trifluoromethyl, methoxy, hydroxymethyl, methoxyamino, methylthio,trifluoromethoxy, fluoro, and chloro;

R² is Z⁰—Q;

Z⁰ is a covalent single bond;

Q is selected from the group consisting of phenyl, 2-thienyl, 2-furyl,2-pyrrolyl, 2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl, and3-pyridyl, wherein a carbon adjacent to the carbon at the point ofattachment is optionally substituted by R⁹, the other carbon adjacent tothe carbon at the point of attachment is optionally substituted by R¹³,a carbon adjacent to R⁹ and two atoms from the carbon at the point ofattachment is optionally substituted by R¹⁰, a carbon adjacent to R¹³and two atoms from the carbon at the point of attachment is optionallysubstituted by R¹², and any carbon adjacent to both R¹⁰ and R¹² isoptionally substituted by R¹¹;

R⁹, R¹¹, and R¹³ are independently selected from the group consisting ofhydrido, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino,N,N-dimethylamino, methylthio, trifluoromethyl, pentafluoroethyl,2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl,N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl,1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, carboxy, andcyano;

R¹⁰ and R¹² are independently selected from the group consisting ofhydrido, amidino, amidocarbonyl, N-methylamidocarbonyl, guanidino,methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, 1-hydroxyethyl,2-hydroxyethyl, carboxy, carboxymethyl, amino, acetamido,trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl,trifluoroacetamido, aminomethyl, N-methylamino, dimethylamino,amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl,methoxycarbonyl, fluoro, chloro, bromo, and cyano;

Y⁰ is selected from the group of formulas consisting of:

R¹⁶, R¹⁷, R¹⁸, and R¹⁹ are independently selected from the groupconsisting of hydrido, methyl, ethyl, amidino, guanidino, methoxy,hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino,dimethylamino, methylthio, ethylthio, trifluoromethylthio,methylsulfinyl, methylsulfonyl, trifluoromethyl, pentafluoroethyl,2,2,2-trifluoroethyl, trifluoromethoxy, fluoro, chloro, amidosulfonyl,N-methylamidosulfonyl, hydroxymethyl, carboxy, and cyano.

The compounds of this invention can be used in anticoagulant therapy forthe treatment and prevention of a variety of thrombotic conditionsincluding coronary artery and cerebrovascular disease. The compounds ofthis invention can be used to inhibit serine protease associated withthe coagulation cascade and factors II, VII, VIII, IX, X, XI, or XII.The compounds of the invention can inhibit the formation of bloodplatelet aggregates, inhibit the formation of fibrin, inhibit thrombusformation, and inhibiting embolus formation in a mammal, in blood, inblood products, and in mammalian organs. The compounds also can be usedfor treating or preventing unstable angina, refractory angina,myocardial infarction, transient ischemic attacks, atrial fibrillation,thrombotic stroke, embolic stroke, deep vein thrombosis, disseminatedintravascular coagulation, ocular build up of fibrin, and reocclusion orrestenosis of recanalized vessels in a mammal. The compounds can also beused in prophylactic treatment of subjects who are at risk of developingsuch disorders. The compounds can be used to lower the risk ofatherosclerosis. The compounds of Formula (I) would also be useful inprevention of cerebral vascular accident (CVA) or stroke.

Besides being useful for human treatment, these compounds are alsouseful for veterinary treatment of companion animals, exotic animals andfarm animals, including mammals, rodents, and the like. More preferredanimals include horses, dogs, and cats.

In yet another embodiment of the present invention, the novel compoundsare selected from the compounds set forth in Examples 1 through Example19 and Tables 1.

The use of generic terms in the description of the compounds are hereindefined for clarity.

Standard single letter elemental symbols are used to represent specifictypes of atoms unless otherwise defined. The symbol “C” represents acarbon atom. The symbol “O” represents an oxygen atom. The symbol “N”represents a nitrogen atom. The symbol “P” represents a phosphorus atom.The symbol “S” represents a sulfur atom. The symbol “H” represents ahydrido atom. Double letter elemental symbols are used as defined forthe elements of the periodical table (i.e., Cl represents chlorine, Serepresents selenium, etc.).

As utilized herein, the term “alkyl”, either alone or within other termssuch as “haloalkyl” and “alkylthio”, means an acyclic alkyl radicalcontaining from 1 to about 10, preferably from 3 to about 8 carbon atomsand more preferably 3 to about 6 carbon atoms. Said alkyl radicals maybe optionally substituted with groups as defined below. Examples of suchradicals include methyl, ethyl, chloroethyl, hydroxyethyl, n-propyl,oxopropyl, isopropyl, n-butyl, cyanobutyl, isobutyl, sec-butyl,tert-butyl, pentyl, aminopentyl, iso-amyl, hexyl, octyl and the like.

The term “alkenyl” refers to an unsaturated, acyclic hydrocarbon radicalin so much as it contains at least one double bond. Such alkenylradicals contain from about 2 to about 10 carbon atoms, preferably fromabout 3 to about 8 carbon atoms and more preferably 3 to about 6 carbonatoms. Said alkenyl radicals may be optionally substituted with groupsas defined below. Examples of suitable alkenyl radicals includepropenyl, 2-chloropropenyl, buten-1-yl, isobutenyl, penten-1-yl,2-2-methylbuten-1-yl, 3-methylbuten-1-yl, hexen-1-yl,3-hydroxyhexen-1-yl, hepten-1-yl, and octen-1-yl, and the like.

The term “alkynyl” refers to an unsaturated, acyclic hydrocarbon radicalin so much as it contains one or more triple bonds, such radicalscontaining about 2 to about 10 carbon atoms, preferably having fromabout 3 to about 8 carbon atoms and more preferably having 3 to about 6carbon atoms. Said alkynyl radicals may be optionally substituted withgroups as defined below. Examples of suitable alkynyl radicals includeethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl,pentyn-2-yl, 4-methoxypentyn-2-yl, 3-methylbutyn-1-yl, hexyn-1-yl,hexyn-2-yl, hexyn-3-yl, 3,3-dimethylbutyn-1-yl radicals and the like.

The term “hydrido” denotes a single hydrogen atom (H). This hydridoradical may be attached, for example, to an oxygen atom to form a“hydroxyl” radical, one hydrido radical may be attached to a carbon atomto form a “methine” radical —CH═, or two hydrido radicals may beattached to a carbon atom to form a “methylene” (—CH₂—) radical.

The term “carbon” radical denotes a carbon atom without any covalentbonds and capable of forming four covalent bonds.

The term “cyano” radical denotes a carbon radical having three of fourcovalent bonds shared by a nitrogen atom.

The term “hydroxyalkyl” embraces radicals wherein any one or more of thealkyl carbon atoms is substituted with a hydroxyl as defined above.Specifically embraced are monohydroxyalkyl, dihydroxyalkyl andpolyhydroxyalkyl radicals.

The term “alkanoyl” embraces radicals wherein one or more of theterminal alkyl carbon atoms are substituted with one or more carbonylradicals as defined below. Specifically embraced are monocarbonylalkyland dicarbonylalkyl radicals. Examples of monocarbonylalkyl radicalsinclude formyl, acetyl, and pentanoyl. Examples of dicarbonylalkylradicals include oxalyl, malonyl, and succinyl.

The term “alkylene” radical denotes linear or branched radicals havingfrom 1 to about 10 carbon atoms and having attachment points for two ormore covalent bonds. Examples of such radicals are methylene, ethylene,methylethylene, and isopropylidene.

The term “alkenylene” radical denotes linear or branched radicals havingfrom 2 to about 10 carbon atoms, at least one double bond, and havingattachment points for two or more covalent bonds. Examples of suchradicals are 1,1-vinylidene (CHR═C), 1,2-vinylidene (—CH═CH—), and1,4-butadienyl (—CH═CH—CH═CH—).

The term “halo” means halogens such as fluorine, chlorine, bromine oriodine atoms.

The term “haloalkyl” embraces radicals wherein any one or more of thealkyl carbon atoms is substituted with halo as defined above.Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkylradicals. A monohaloalkyl radical, for one example, may have either abromo, chloro or a fluoro atom within the radical. Dihalo radicals mayhave two or more of the same halo atoms or a combination of differenthalo radicals and polyhaloalkyl radicals may have more than two of thesame halo atoms or a combination of different halo radicals. Morepreferred haloalkyl radicals are “lower haloalkyl” radicals having oneto about six carbon atoms. Examples of such haloalkyl radicals includefluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, trifluoroethyl, pentafluoroethyl,heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.

The term “hydroxyhaloalkyl” embraces radicals wherein any one or more ofthe haloalkyl carbon atoms is substituted with hydroxy as defined above.Examples of “hydroxyhaloalkyl” radicals include hexafluorohydroxypropyl.

The term “haloalkylene radical” denotes alkylene radicals wherein anyone or more of the alkylene carbon atoms is substituted with halo asdefined above. Dihalo alkylene radicals may have two or more of the samehalo atoms or a combination of different halo radicals andpolyhaloalkylene radicals may have more than two of the same halo atomsor a combination of different halo radicals. More preferred haloalkyleneradicals are “lower haloalkylene” radicals having one to about sixcarbon atoms. Examples of “haloalkylene” radicals includedifluoromethylene, tetrafluoroethylene, tetrachloroethylene, alkylsubstituted monofluoromethylene, and aryl substitutedtrifluoromethylene.

The term “haloalkenyl” denotes linear or branched radicals having from 1to about 10 carbon atoms and having one or more double bonds wherein anyone or more of the alkenyl carbon atoms is substituted with halo asdefined above. Dihaloalkenyl radicals may have two or more of the samehalo atoms or a combination of different halo radicals andpolyhaloalkenyl radicals may have more than two of the same halo atomsor a combination of different halo radicals.

The terms “alkoxy” and “alkoxyalkyl” embrace linear or branchedoxy-containing radicals each having alkyl portions of one to about tencarbon atoms, such as methoxy radical. The term “alkoxyalkyl” alsoembraces alkyl radicals having one or more alkoxy radicals attached tothe alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkylradicals. More preferred alkoxy radicals are “lower alkoxy” radicalshaving one to six carbon atoms. Examples of such radicals includemethoxy, ethoxy, propoxy, butoxy, isopropoxy and tert-butoxy alkyls. The“alkoxy” radicals may be further substituted with one or more haloatoms, such as fluoro, chloro or bromo, to provide “haloalkoxy” and“haloalkoxyalkyl” radicals. Examples of such haloalkoxy radicals includefluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy,trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, andfluoropropoxy. Examples of such haloalkoxyalkyl radicals includefluoromethoxymethyl, chloromethoxyethyl, trifluoromethoxymethyl,difluoromethoxyethyl, and trifluoroethoxymethyl.

The terms “alkenyloxy” and “alkenyloxyalkyl” embrace linear or branchedoxy-containing radicals each having alkenyl portions of two to about tencarbon atoms, such as ethenyloxy or propenyloxy radical. The term“alkenyloxyalkyl” also embraces alkenyl radicals having one or morealkenyloxy radicals attached to the alkyl radical, that is, to formmonoalkenyloxyalkyl and dialkenyloxyalkyl radicals. More preferredalkenyloxy radicals are “lower alkenyloxy” radicals having two to sixcarbon atoms. Examples of such radicals include ethenyloxy, propenyloxy,butenyloxy, and isopropenyloxy alkyls. The “alkenyloxy” radicals may befurther substituted with one or more halo atoms, such as fluoro, chloroor bromo, to provide “haloalkenyloxy” radicals. Examples of suchradicals include trifluoroethenyloxy, fluoroethenyloxy,difluoroethenyhloxy, and fluoropropenyloxy.

The term “haloalkoxyalkyl” also embraces alkyl radicals having one ormore haloalkoxy radicals attached to the alkyl radical, that is, to formmonohaloalkoxyalkyl and dihaloalkoxyalkyl radicals. The term“haloalkenyloxy” also embraces oxygen radicals having one or morehaloalkenyloxy radicals attached to the oxygen radical, that is, to formmonohaloalkenyloxy and dihaloalkenyloxy radicals. The term“haloalkenyloxyalkyl” also embraces alkyl radicals having one or morehaloalkenyloxy radicals attached to the alkyl radical, that is, to formmonohaloalkenyloxyalkyl and dihaloalkenyloxyalkyl radicals.

The term “alkylenedioxy” radicals denotes alkylene radicals having atleast two oxygens bonded to a single alkylene group. Examples of“alkylenedioxy” radicals include methylenedioxy, ethylenedioxy,alkylsubstituted methylenedioxy, and arylsubstituted methylenedioxy. Theterm “haloalkylenedioxy” radicals denotes haloalkylene radicals havingat least two oxy groups bonded to a single haloalkyl group. Examples of“haloalkylenedioxy” radicals include difluoromethylenedioxy,tetrafluoroethylenedioxy, tetrachloroethylenedioxy, alkylsubstitutedmonofluoromethylenedioxy, and arylsubstituted monofluoromethylenedioxy.

The term “aryl”, alone or in combination, means a carbocyclic aromaticsystem containing one, two or three rings wherein such rings may beattached together in a pendant manner or may be fused. The term “fused”means that a second ring is present (ie, attached or formed) by havingtwo adjacent atoms in common (ie, shared) with the first ring. The term“fused” is equivalent to the term “condensed”. The term “aryl” embracesaromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indaneand biphenyl.

The term “perhaloaryl” embraces aromatic radicals such as phenyl,naphthyl, tetrahydronaphthyl, indane and biphenyl wherein the arylradical is substituted with 3 or more halo radicals as defined below.

The term “heterocyclyl” embraces saturated and partially saturatedheteroatom-containing ring-shaped radicals having from 4 through 15 ringmembers, herein referred to as “C4-C15 heterocyclyl” selected fromcarbon, nitrogen, sulfur and oxygen, wherein at least one ring atom is aheteroatom. Heterocyclyl radicals may contain one, two or three ringswherein such rings may be attached in a pendant manner or may be fused.Examples of saturated heterocyclic radicals include saturated 3 to6-membered heteromonocylic group containing 1 to 4 nitrogen atoms[e.g.pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.]; saturated3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atomsand 1 to 3 nitrogen atoms [e.g. morpholinyl, etc.]; saturated 3 to6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1to 3 nitrogen atoms [e.g., thiazolidinyl, etc.]. Examples of partiallysaturated heterocyclyl radicals include dihydrothiophene, dihydropyran,dihydrofuran and dihydrothiazole. Non-limiting examples of heterocyclicradicals include 2-pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl,1,3-dioxolanyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4-dioxanyl,morpholinyl, 1,4-dithianyl, thiomorpholinyl, and the like.

The term “heteroaryl” embraces fully unsaturated heteroatom-containingring-shaped aromatic radicals having from 5 through 15 ring membersselected from carbon, nitrogen, sulfur and oxygen, wherein at least onering atom is a heteroatom. Heteroaryl radicals may contain one, two orthree rings wherein such rings may be attached in a pendant manner ormay be fused. Examples of “heteroaryl” radicals, include unsaturated 5to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms,for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl,3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl[e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.]tetrazolyl [e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.], etc.; unsaturatedcondensed heterocyclic group containing 1 to 5 nitrogen atoms, forexample, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl,isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g.,tetrazolo [1,5-b]pyridazinyl, etc.], etc.; unsaturated 3 to 6-memberedheteromonocyclic group containing an oxygen atom, for example, pyranyl,2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclicgroup containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.;unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl,isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl, etc.] etc.; unsaturated condensed heterocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.benzoxazolyl, benzoxadiazolyl, etc.]; unsaturated 5 to 6-memberedheteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g.,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.] etc.;unsaturated condensed heterocyclic group containing 1 to 2 sulfur atomsand 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl,etc.] and the like. The term also embraces radicals where heterocyclicradicals are fused with aryl radicals. Examples of such fused bicyclicradicals include benzofuran, benzothiophene, and the like. Said“heterocyclyl” group may have 1 to 3 substituents as defined below.Preferred heterocyclic radicals include five to twelve membered fused orunfused radicals. Non-limiting examples of heteroaryl radicals includepyrrolyl, pyridinyl, pyridyloxy, pyrazolyl, triazolyl, pyrimidinyl,pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl,furanyl, tetrazolyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl,pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl,1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyrazinyl, piperazinyl,1,3,5-trifazinyl, 1,3,5-trithianyl, benzo(b)thiophenyl, benzimidazoyl,quinolinyl, tetraazolyl, and the like.

The term “sulfonyl”, whether used alone or linked to other terms such asalkylsulfonyl, denotes respectively divalent radicals —SO₂—.“Alkylsulfonyl”, embraces alkyl radicals attached to a sulfonyl radical,where alkyl is defined as above. “Alkylsulfonylalkyl”, embracesalkylsulfonyl radicals attached to an alkyl radical, where alkyl isdefined as above. “Haloalkylsulfonyl”, embraces haloalkyl radicalsattached to a sulfonyl radical, where haloalkyl is defined as above.“Haloalkylsulfonylalkyl”, embraces haloalkylsulfonyl radicals attachedto an alkyl radical, where alkyl is defined as above. The term“aminosulfonyl” denotes an amino radical attached to a sulfonyl radical.

The term “sulfinyl”, whether used alone or linked to other terms such asalkylsulfinyl, denotes respectively divalent radicals —S(O)—.“Alkylsulfinyl”, embraces alkyl radicals attached to a sulfinyl radical,where alkyl is defined as above. “Alkylsulfinylalkyl”, embracesalkylsulfinyl radicals attached to an alkyl radical, where alkyl isdefined as above. “Haloalkylsulfinyl”, embraces haloalkyl radicalsattached to a sulfinyl radical, where haloalkyl is defined as above.“Haloalkylsulfinylalkyl”, embraces haloalkylsulfinyl radicals attachedto an alkyl radical, where alkyl is defined as above.

The term “aralkyl” embraces aryl-substituted alkyl radicals. Preferablearalkyl radicals are “lower aralkyl” radicals having aryl radicalsattached to alkyl radicals having one to six carbon atoms. Examples ofsuch radicals include benzyl, diphenylmethyl, triphenylmethyl,phenylethyl and diphenylethyl. The terms benzyl and phenylmethyl areinterchangeable.

The term “heteroaralkyl” embraces heteroaryl-substituted alkyl radicalswherein the heteroaralkyl radical may be additionally substituted withthree or more substituents as defined above for aralkyl radicals. Theterm “perhaloaralkyl” embraces aryl-substituted alkyl radicals whereinthe aralkyl radical is substituted with three or more halo radicals asdefined above.

The term “aralkylsulfinyl”, embraces aralkyl radicals attached to asulfinyl radical, where aralkyl is defined as above.“Aralkylsulfinylalkyl”, embraces aralkylsulfinyl radicals attached to analkyl radical, where alkyl is defined as above.

The term “aralkylsulfonyl”, embraces aralkyl radicals attached to asulfonyl radical, where aralkyl is defined as above.“Aralkylsulfonylalkyl”, embraces aralkylsulfonyl radicals attached to analkyl radical, where alkyl is defined as above.

The term “cycloalkyl” embraces radicals having three to 15 carbon atoms.More preferred cycloalkyl radicals are “lower cycloalkyl” radicalshaving three to seven carbon atoms. Examples include radicals such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Theterm cycloalkyl embraces radicals having seven to 15 carbon atoms andhaving two to four rings. Examples include radicals such as norbornyl(i.e., bicyclo[2.2.1]heptyl) and adamantyl. The term “cycloalkylalkyl”embraces cycloalkyl-substituted alkyl radicals. Preferablecycloalkylalkyl radicals are “lower cycloalkylalkyl” radicals havingcycloalkyl radicals attached to alkyl radicals having one to six carbonatoms. Examples of such radicals include cyclohexylhexyl. The term“cycloalkenyl” embraces radicals having three to ten carbon atoms andone or more carbon-carbon double bonds. Preferred cycloalkenyl radicalsare “lower cycloalkenyl” radicals having three to seven carbon atoms.Examples include radicals such as cyclobutenyl, cyclopentenyl,cyclohexenyl and cycloheptenyl. The term “halocycloalkyl” embracesradicals wherein any one or more of the cycloalkyl carbon atoms issubstituted with halo as defined above. Specifically embraced aremonohalocycloalkyl, dihalocycloalkyl and polyhalocycloalkyl radicals. Amonohalocycloalkyl radical, for one example, may have either a bromo,chloro or a fluoro atom within the radical. Dihalo radicals may have twoor more of the same halo atoms or a combination of different haloradicals and polyhalocycloalkyl radicals may have more than two of thesame halo atoms or a combination of different halo radicals. Morepreferred halocycloalkyl radicals are “lower halocycloalkyl” radicalshaving three to about eight carbon atoms. Examples of suchhalocycloalkyl radicals include fluorocyclopropyl, difluorocyclobutyl,trifluorocyclopentyl, tetrafluorocyclohexyl, and dichlorocyclopropyl.The term “halocycloalkenyl” embraces radicals wherein any one or more ofthe cycloalkenyl carbon atoms is substituted with halo as defined above.Specifically embraced are monohalocycloalkenyl, dihalocycloalkenyl andpolyhalocycloalkenyl radicals.

The term “cycloalkoxy” embraces cycloalkyl radicals attached to an oxyradical. Examples of such radicals includes cyclohexoxy andcyclopentoxy. The term “cycloalkoxyalkyl” also embraces alkyl radicalshaving one or more cycloalkoxy radicals attached to the alkyl radical,that is, to form monocycloalkoxyalkyl and dicycloalkoxyalkyl radicals.Examples of such radicals include cyclohexoxyethyl. The “cycloalkoxy”radicals may be further substituted with one or more halo atoms, such asfluoro, chloro or bromo, to provide “halocycloalkoxy” and“halocycloalkoxyalkyl” radicals.

The term “cycloalkylalkoxy” embraces cycloalkyl radicals attached to analkoxy radical. Examples of such radicals includes cyclohexylmethoxy andcyclopentylmethoxy.

The term “cycloalkenyloxy” embraces cycloalkenyl radicals attached to anoxy radical. Examples of such radicals includes cyclohexenyloxy andcyclopentenyloxy. The termr “cycloalkenyloxyalkyl” also embraces alkylradicals having one or more cycloalkenyloxy radicals attached to thealkyl radical, that is, to form monocycloalkenyloxyalkyl anddicycloalkenyloxyalkyl radicals. Examples of such radicals includecyclohexenyloxyethyl. The “cycloalkenyloxy” radicals may be furthersubstituted with one or more halo atoms, such as fluoro, chloro orbromo, to provide “halocycloalkenyloxy” and “halocycloalkenyloxyalkyl”radicals.

The term “cycloalkylenedioxy” radicals denotes cycloalkylene radicalshaving at least two oxygens bonded to a single cycloalkylene group.Examples of “alkylenedioxy” radicals include 1,2-dioxycyclohexylene.

The term “cycloalkylsulfinyl”, embraces cycloalkyl radicals attached toa sulfinyl radical, where cycloalkyl is defined as above.“Cycloalkylsulfinylalkyl”, embraces cycloalkylsulfinyl radicals attachedto an alkyl radical, where alkyl is defined as above. The term“Cycloalkylsulfonyl”, embraces cycloalkyl radicals attached to asulfonyl radical, where cycloalkyl is defined as above.“Cycloalkylsulfonylalkyl”, embraces cycloalkylsulfonyl radicals attachedto an alkyl radical, where alkyl is defined as above.

The term “cycloalkylalkanoyl” embraces radicals wherein one or more ofthe cycloalkyl carbon atoms are substituted with one or more carbonylradicals as defined below. Specifically embraced aremonocarbonylcycloalkyl and dicarbonylcycloalkyl radicals. Examples ofmonocarbonylcycloalkyl radicals include cyclohexylcarbonyl,cyclohexylacetyl, and cyclopentylcarbonyl. Examples ofdicarbonylcycloalkyl radicals include 1,2-dicarbonylcyclohexane.

The term “alkylthio” embraces radicals containing a linear or branchedalkyl radical, of one to ten carbon atoms, attached to a divalent sulfuratom. More preferred alkylthio radicals are “lower alkylthio” radicalshaving one to six carbon atoms. An example of “lower alkylthio” ismethylthio (CH₃—S—). The “alkylthio” radicals may be further substitutedwith one or more halo atoms, such as fluoro, chloro or bromo, to provide“haloalkylthio” radicals. Examples of such radicals includefluoromethylthio, chloromethylthio, trifluoromethylthio,difluoromethylthio, trifluoroethylthio, fluoroethylthio,tetrafluoroethylthio, pentafluoroethylthio, and fluoropropylthio.

The term “alkyl aryl amino” embraces radicals containing a linear orbranched alkyl radical, of one to ten carbon atoms, and one aryl radicalboth attached to an amino radical. Examples includeN-methyl-4-methoxyaniline, N-ethyl-4-methoxyaniline, andN-methyl-4-trifluoromethoxyaniline.

The terms alkylamino denotes “monoalkylamino” and “dialkylamino”containing one or two alkyl radicals, respectively, attached to an aminoradical.

The terms arylamino denotes “monoarylamino” and “diarylamino” containingone or two aryl radicals, respectively, attached to an amino radical.Examples of such radicals include N-phenylamino and N-naphthylamino.

The term “aralkylamino”, embraces aralkyl radicals attached to an aminoradical, where aralkyl is defined as above. The term aralkylaminodenotes “monoaralkylamino” and “diaralkylamino” containing one or twoaralkyl radicals, respectively, attached to an amino radical. The termaralkylamino further denotes “monoaralkyl monoalkylamino” containing onearalkyl radical and one alkyl radical attached to an amino radical.

The term “arylsulfinyl” embraces radicals containing an aryl radical, asdefined above, attached to a divalent S(O) atom. The term“arylsulfinylalkyl” denotes arylsulfinyl radicals attached to a linearor branched alkyl radical, of one to ten carbon atoms.

The term “arylsulfonyl”, embraces aryl radicals attached to a sulfonylradical, where aryl is defined as above. “arylsulfonylalkyl”, embracesarylsulfonyl radicals attached to an alkyl radical, where alkyl isdefined as above. The term “heteroarylsulfinyl” embraces radicalscontaining an heteroaryl radical, as defined above, attached to adivalent S(O) atom. The term “heteroarylsulfinylalkyl” denotesheteroarylsulfinyl radicals attached to a linear or branched alkylradical, of one to ten carbon atoms. The term “Heteroarylsulfonyl”,embraces heteroaryl radicals attached to a sulfonyl radical, whereheteroaryl is defined as above. “Heteroarylsulfonylalkyl”, embracesheteroarylsulfonyl radicals attached to an alkyl radical, where alkyl isdefined as above.

The term “aryloxy” embraces aryl radicals, as defined above, attached toan oxygen atom. Examples of such radicals include phenoxy,4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy,3-chloro-4-ethylenoxy, 3,4-dichlorophenoxy, 4-methylphenoxy,3-trifluoromethoxyphenoxy, 3-trifluoromethylphenoxy, 4-fluorophenoxy,3,4-dimethylphenoxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy,4-fluoro-3-methylphenoxy, 5,6,7,8-tetrahydronaphthyloxy,3-isopropylphenoxy, 3-cyclopropylphenoxy, 3-ethylphenoxy,3-pentafluoro-4-ethylenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, and4-tert-butylphenoxy.

The term “aroyl” embraces aryl radicals, as defined above, attached toan carbonyl radical as defined above. Examples of such radicals includebenzoyl and toluoyl.

The term “aralkanoyl” embraces aralkyl radicals, as defined herein,attached to an carbonyl radical as defined above. Examples of suchradicals include, for example, phenylacetyl.

The term “aralkoxy” embraces oxy-containing aralkyl radicals attachedthrough an oxygen atom to other radicals. More preferred aralkoxyradicals are “lower aralkoxy” radicals having phenyl radicals attachedto lower alkoxy radical as described above. Examples of such radicalsinclude benzyloxy, 1-phenylethoxy, 3-trifluoromethoxybenzyloxy,3-trifluoromethylbenzyloxy, 3,5-difluorobenyloxy, 3-bromobenzyloxy,4-propylbenzyloxy, 2-fluoro-3-trifluoromethylbenzyloxy, and2-phenylethoxy.

The term “aryloxyalkyl” embraces aryloxy radicals, as defined above,attached to an alkyl group. Examples of such radicals includephenoxymethyl.

The term “haloaryloxyalkyl” embraces aryloxyalkyl radicals, as definedabove, wherein one to five halo radicals are attached to an aryloxygroup.

The term “heteroaroyl” embraces heteroaryl radicals, as defined above,attached to an carbonyl radical as defined above. Examples of suchradicals include furoyl and nicotinyl.

The term “heteroaralkanoyl” embraces heteroaralkyl radicals, as definedherein, attached to an carbonyl radical as defined above. Examples ofsuch radicals include, for example, pyridylacetyl and furylbutyryl.

The term “heteroaralkoxy” embraces oxy-containing heteroaralkyl radicalsattached through an oxygen atom to other radicals. More preferredheteroaralkoxy radicals are “lower heteroaralkoxy” radicals havingheteroaryl radicals attached to lower alkoxy radical as described above.

The term “haloheteroaryloxyalkyl” embraces heteroaryloxyalkyl radicals,as defined above, wherein one to four halo radicals are attached to anheteroaryloxy group.

The term “heteroarylamino” embraces heterocyclyl radicals, as definedabove, attached to an amino group. Examples of such radicals includepyridylamino.

The term “heteroarylaminoalkyl” embraces heteroarylamino radicals, asdefined above, attached to an alkyl group. Examples of such radicalsinclude pyridylmethylamino.

The term “heteroaryloxy” embraces heterocyclyl radicals, as definedabove, attached to an oxy group. Examples of such radicals include2-thiophenyloxy, 2-pyrimidyloxy, 2-pyridyloxy, 3-pyridyloxy, and4-pyridyloxy.

The term “heteroaryloxyalkyl” embraces heteroaryloxy radicals, asdefined above, attached to an alkyl group. Examples of such radicalsinclude 2-pyridyloxymethyl, 3-pyridyloxyethyl, and 4-pyridyloxymethyl.

The term “arylthio” embraces aryl radicals, as defined above, attachedto an sulfur atom. Examples of such radicals include phenylthio.

The term “arylthioalkyl” embraces arylthio radicals, as defined above,attached to an alkyl group. Examples of such radicals includephenylthiomethyl.

The term “alkylthioalkyl” embraces alkylthio radicals, as defined above,attached to an alkyl group. Examples of such radicals includemethylthiomethyl. The term “alkoxyalkyl” embraces alkoxy radicals, asdefined above, attached to an alkyl group. Examples of such radicalsinclude methoxymethyl.

The term “carbonyl” denotes a carbon radical having two of the fourcovalent bonds shared with an oxygen atom. The term “carboxy” embraces ahydroxyl radical, as defined above, attached to one of two unsharedbonds in a carbonyl group. The term “carboxamide” embraces amino,monoalkylamino, dialkylamino, monocycloalkylamino, alkylcycloalkylamino,and dicycloalkylamino radicals, attached to one of two unshared bonds ina carbonyl group. The term “carboxamidoalkyl” embraces carboxamideradicals, as defined above, attached to an alkyl group. The term“carboxyalkyl” embraces a carboxy radical, as defined above, attached toan alkyl group. The term “carboalkoxy” embraces alkoxy radicals, asdefined above, attached to one of two unshared bonds in a carbonylgroup. The term “carboaralkoxy” embraces aralkoxy radicals, as definedabove, attached to one of two unshared bonds in a carbonyl group. Theterm “monocarboalkoxyalkyl” embraces one carboalkoxy radical, as definedabove, attached to an alkyl group. The term “dicarboalkoxyalkyl”embraces two carboalkoxy radicals, as defined above, attached to analkylene group. The term “monocyanoalkyl” embraces one cyano radical, asdefined above, attached to an alkyl group. The term “dicyanoalkylene”embraces two cyano radicals, as defined above, attached to an alkylgroup. The term “carboalkoxycyanoalkyl” embraces one cyano radical, asdefined above, attached to an carboalkoxyalkyl group.

The term “acyl”, alone or in combination, means a carbonyl orthionocarbonyl group bonded to a radical selected from, for example,hydrido, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkoxyalkyl,haloalkoxy, aryl, heterocyclyl, heteroaryl, alkylsulfinylalkyl,alkylsulfonylalkyl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,alkylthio, arylthio, amino, alkylamino, dialkylamino, aralkoxy,arylthio, and alkylthioalkyl. Examples of “acyl” are formyl, acetyl,benzoyl, trifluoroacetyl, phthaloyl, malonyl, nicotinyl, and the like.The term “haloalkanoyl” embraces one or more halo radicals, as definedherein, attached to an alkanoyl radical as defined above. Examples ofsuch radicals include, for example, chloroacetyl, trifluoroacetyl,bromopropanoyl, and heptafluorobutanoyl.

The term “phosphono” embraces a pentavalent phosphorus attached with twocovalent bonds to an oxygen radical. The term “dialkoxyphosphono”denotes two alkoxy radicals, as defined above, attached to a phosphonoradical with two covalent bonds. The term “diaralkoxyphosphono” denotestwo aralkoxy radicals, as defined above, attached to a phosphono radicalwith two covalent bonds. The term “dialkoxyphosphonoalkyl” denotesdialkoxyphosphono radicals, as defined above, attached to an alkylradical. The term “diaralkoxyphosphonoalkyl” denotes diaralkoxyphosphonoradicals, as defined above, attached to an alkyl radical.

The term “amino” denotes a nitrogen atom containing two substituentssuch as hydrido, hydroxy or alkyl and having one covalent bond availablefor bonding to a single atom such as carbon. Examples of such aminoradicals include, for example, —NH₂, —NHCH₃, —NHOH, and —NHOCH₃. Theterm “imino” denotes a nitrogen atom containing one substituent such ashydrido, hydroxy or alkyl and having two covalent bonds available forbonding to a single atom such as carbon. Examples of such imino radicalsinclude, for example, ═NH, ═NCH, ═NOH, and ═NOCH₃. The term “iminocarbonyl” denotes a carbon radical having two of the four covalent bondsites shared with an imino group. Examples of such imino carbonylradicals include, for example, C═NH, C═NCH₃, C═NOH, and C═NOCH₃. Theterm “amidino” embraces a substituted or unsubstituted amino groupbonded to one of two available bonds of an iminocarbonyl radical.Examples of such amidino radicals include, for example, NH₂—C═NH,NH₂—C═NCH₃, NH₂—C═NOCH₃ and CH₃NH—C═NOH. The term “guanidino” denotes anamidino group bonded to an amino group as defined above where said aminogroup can be bonded to a third group. Examples of such guanidinoradicals include, for example, NH₂—C(NH)—NH—, NH₂—C(NCH₃)—NH—,NH₂—C(NOCH₃)—NH—, and CH₃NH—C(NOH)—NH—.

The term “sulfonium” denotes a positively charged trivalent sulfur atomwhere said sulfur is substituted with three carbon based groups such asalkyl, alkenyl, aralkyl, or aryl. The term “dialkyl sulfonium” denotes asulfonium group where said sulfur is substituted with two alkyl groups.Examples of such dialkylsulfonium radicals include, for example,(CH₃)₂S⁺—. The term “dialkyl sulfonium alkyl” denotes a dialkylsulfonium group where said group is bonded to one bond of an alkylenegroup as defined above. Examples of such dialkylsulfoniumalkyl radicalsinclude (CH₃)₂S⁺—CH₂CH₂—.

The term “phosphonium” denotes a positively charged tetravalentphosphorus atom where said phosphorus is substituted with four carbonbased groups such as alkyl, alkenyl, aralkyl, or aryl. The term“trialkyl phosphonium” denotes a phosphonium group where said phosphorusis substituted with three alkyl groups. Examples of suchtrialkylphosphonium radicals include, for example, (CH₃)₃P⁺.

Said “alkyl”, “alkenyl”, “alkynyl”, “alkanoyl”, “alkylene”,“alkenylene”, “hydroxyalkyl”, “haloalkyl”, “haloalkylene”,“haloalkenyl”, “alkoxy”, “alkenyloxy”, “alkenyloxyalkyl”, “alkoxyalkyl”,“aryl”, “perhaloaryl”, “haloalkoxy”, “haloalkoxyalkyl”,“haloalkenyloxy”, “haloalkenyloxyalkyl”, “alkylenedioxy”,“haloalkylenedioxy”, “heterocyclyl”, “heteroaryl”, “hydroxyhaloalkyl”,“alkylsulfonyl”, “haloalkylsulfonyl”, “alkylsulfonylalkyl”,“haloalkylsulfonylalkyl”, “alkylsulfinyl”, “alkylsulfinylalkyl”,“haloalkylsulfinylalkyl”, “aralkyl”, “heteroaralkyl”, “perhaloaralkyl”,“aralkylsulfonyl”, “aralkylsulfonylalkyl”, “aralkylsulfinyl”,“aralkylsulfinylalkyl”, “cycloalkyl”, “cycloalkylalkanoyl”,“cycloalkylalkyl”, “cycloalkenyl”, “halocycloalkyl”, “halocycloalkenyl”,“cycloalkylsulfinyl”, “cycloalkylsulfinylalkyl”, “cycloalkylsulfonyl”,“cycloalkylsulfonylalkyl”, “cycloalkoxy”, “cycloalkoxyalkyl”,“cycloalkylalkoxy”, “cycloalkenyloxy”, “cycloalkenyloxyalkyl”,“cycloalkylenedioxy”, “halocycloalkoxy”, “halocycloalkoxyalkyl”,“halocycloalkenyloxy”, “halocycloalkenyloxyalkyl”, “alkylthio”,“haloalkylthio”, “alkylsulfinyl”, “amino”, “oxy”, “thio”, “alkylamino”,“arylamino”, “aralkylamino”, “arylsulfinyl”, “arylsulfinylalkyl”,“arylsulfonyl”, “arylsulfonylalkyl”, “heteroarylsulfinyl”,“heteroarylsulfinylalkyl”, “heteroarylsulfonyl”,“heteroarylsulfonylalkyl”, “heteroarylamino”, “heteroarylaminoalkyl”,“heteroaryloxy”, “heteroaryloxylalkyl”, “aryloxy”, “aroyl”,“aralkanoyl”, “aralkoxy”, “aryloxyalkyl”, “haloaryloxyalkyl”,“heteroaroyl”, “heteroaralkanoyl”, “heteroaralkoxy”,“heteroaralkoxyalkyl”, “arylthio”, “arylthioalkyl”, “alkoxyalkyl”,“acyl”, “amidino”, “guanidino”, “dialkylsulfonium”,“trialkylphosphonium”, and “dialkylsulfoniumalkyl” groups defined abovemay optionally have 1 or more non-hydrido substituents such as amidino,guanidino, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl,perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl,aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl,cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl,cycloalkylsulfonylalkyl, heteroarylamino,N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, heteroaryloxy,heteroaryloxylalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl,haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy,cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl,cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl,halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio,nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino,aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl,alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl,heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl,alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl,alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkylamidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl,arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl,arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl,heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl,heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy,alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl,cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lowercycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy,hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, aminoalkyl,hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy,aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl,heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl,heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl,carboalkoxy, alkoxycarbonyl, carboaralkoxy, carboxamido,carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl,diaralkoxyphosphono, and diaralkoxyphosphonoalkyl.

The term “spacer” can include a covalent bond and a linear moiety havinga backbone of 1 to 7 contiguous atoms. The spacer may have 1 to 7 atomsof a univalent or multi-valent chain. Univalent chains may beconstituted by a radical selected from ═C(H)—, ═C(R^(2a))—, —O—, —S—,—S(O)—, —S(O)₂—, —NH—, —N(R^(2a))—, —N═, —CH(OH)—, ═C(OH)—,—CH(OR^(2a))—, ═C(OR^(2a))—, and —C(O)— wherein R^(2a) is selected fromalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, aryloxyalkyl,alkoxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl,haloalkyl, haloalkenyl, haloalkoxyalkyl, perhaloaralkyl,heteroarylalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, andheteroarylalkenyl. Multi-valent chains may consist of a straight chainof 1 or 2 or 3 or 4 or 5 or 6 or 7 atoms or a straight chain of 1 or 2or 3 or 4 or 5 or 6 atoms with a side chain. The chain may beconstituted of one or more radicals selected from: lower alkylene, loweralkenyl, —O—, —O—CH₂—, —S—CH₂—, —CH₂CH₂—, ethenyl, —CH═CH(OH)—, —OCH₂O—,—O(CH₂)₂O—, —NHCH₂—, —OCH(R^(2a))O—, —O(CH₂CHR^(2a))O—, —OCF₂O—,—O(CF₂)₂O—, —S—, —S(O)—, —S(O)₂—, —N(H)—, —N(H)O—, —N(R^(2a))O—,—N(R^(2a))—, —C(O)—, —C(O)NH—, —C(O)NR^(2a)—, —N═, —OCH₂—, —SCH₂—,S(O)CH₂—, —CH₂C(O)—, —CH(OH)—, ═C(OH)—, —CH(OR^(2a))—, ═C(OR^(2a))—,S(O)₂CH₂—, and —NR CR₂— and many other radicals defined above orgenerally known or ascertained by one of skill-in-the art. Side chainsmay include substituents such as 1 or more non-hydrido substituents suchas amidino, guanidino, dialkylsulfonium, trialkylphosphonium,dialkylsulfoniumalkyl, perhaloaralkyl, aralkylsulfonyl,aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl,halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl,cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl,heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl,heteroaryloxy, heteroaryloxylalkyl, haloalkylthio, alkanoyloxy, alkoxy,alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy,cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy,cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl,hydroxy, amino, thio, nitro, lower alkylamino, alkylthio,alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl,heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl,arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl,heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl,haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido,alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkylamidosulfonyl, monoarylamidosulfonyl, arylsulfonamido,diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl,arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl,alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl,haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky,alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkenyl, lowercycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl,haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, aminoalkyl,hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy,aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl,heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl,heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl,carboalkoxy, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano,carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, anddiaralkoxyphosphonoalkyl.

Compounds of the present invention can exist in tautomeric, geometric orstereoisomeric forms. The present invention contemplates all suchcompounds, including cis- and trans-geometric isomers, E- andZ-geometric isomers, R- and S-enantiomers, diastereomers, d-isomers,l-isomers, the racemic mixtures thereof and other mixtures thereof, asfalling within the scope of the invention. Pharmaceutically acceptablesales of such tautomeric, geometric or stereoisomeric forms are alsoincluded within the invention.

The terms “cis” and “trans” denote a form of geometric isomerism inwhich two carbon atoms connected by a double bond will each have ahydrogen atom on the same side of the double bond (“cis”) or on oppositesides of the double bond (“trans”).

Some of the compounds described contain alkenyl groups, and are meant toinclude both cis and trans or “E” and “Z” geometric forms.

Some of the compounds described contain one or more stereocenters andare meant to include R, S, and mixtures of R and S forms for eachstereocenter present.

Some of the compounds described herein may contain one or more ketonicor aldehydic carbonyl groups or combinations thereof alone or as part ofa heterocyclic ring system. Such carbonyl groups may exist in part orprincipally in the “keto” form and in part or principally as one or more“enol” forms of each aldehyde and ketone group present. Compounds of thepresent invention having aldehydic or ketonic carbonyl groups are meantto include both “keto” and “enol” tautomeric forms.

Some of the compounds described herein may contain one or more amidecarbonyl groups or combinations thereof alone or as part of aheterocyclic ring system. Such carbonyl groups may exist in part orprincipally in the “keto” form and in part or principally as one or more“enol” forms of each amide group present. Compounds of the presentinvention having amidic carbonyl groups are meant to include both “keto”and “enol” tautomeric forms. Said amide carbonyl groups may be both oxo(C═O) and thiono (C═S) in type.

Some of the compounds described herein may contain one or more imine orenamine groups or combinations thereof. Such groups may exist in part orprincipally in the “imine” form and in part or principally as one ormore “enamine” forms of each group present. Compounds of the presentinvention having said imine or enamine groups are meant to include both“imine” and “enamine” tautomeric forms.

The present invention also comprises a treatment and prophylaxis inanticoagulant therapy for the treatment and prevention of a variety ofthrombotic conditions including coronary artery and cerebrovasculardisease in a subject, comprising administering to the subject havingsuch disorder a therapeutically-effective amount of a compound ofFormula (I):

or a pharmaceutically-acceptable salt thereof.

As a further embodiment, compounds of the present invention of Formula(I) or a pharmaceutically-acceptable salt thereof as defined above,comprise a treatment and prophylaxis of coronary artery disease,cerebrovascular disease and other coagulation cascade related disordersin a subject, comprising administering to the subject having suchdisorder a therapeutically-effective amount of compounds of formula (I)of the present invention or a pharmaceutically-acceptable salt thereof.

Compounds of the present invention of Formula (I) or apharmaceutically-acceptable salt thereof can also be used wheneverinhibition of blood coagulation is required such as to preventcoagulation of stored whole blood and to prevent coagulation in otherbiological samples for testing or storage. Thus coagulation inhibitorsof the present inhibition can be added to or contacted with stored wholeblood and any medium containing or suspected of containing plasmacoagulation factors and in which it is desired that blood coagulation beinhibited, e.g. when contacting the mammal's blood with materialselected from the group consisting of vascular grafts, stents,orthopedic prothesis, cardiac prosthesis, and extracorporeal circulationsystems.

Compounds of Formula (I) are capable of inhibiting activity of serineproteases related to the coagulation cascade, and thus could be used inthe manufacture of a medicament, a method for the prophylactic ortherapeutic treatment of diseases mediated by coagulation cascade serineproteases, such as inhibiting the formation of blood plateletaggregates, inhibiting the formation of fibrin, inhibiting thrombusformation, and inhibiting embolus formation in a mammal, in blood, inblood products, and in mammalian organs. The compounds also can be usedfor treating or preventing unstable angina, refractory angina,myocardial infarction, transient ischemic attacks, atrial fibrillation,thrombotic stroke, embolic stroke, deep vein thrombosis, disseminatedintravascular coagulation, ocular build up of fibrin, and reocclusion orrestenosis of recanalized vessels in a mammal. The compounds also can beused to study the mechanism of action of coagulation cascade serineproteases to enable the design of better inhibitors and development ofbetter assay methods. The compounds of Formula (I) would be also usefulin prevention of cerebral vascular accident (CVA) or stroke.

Also included in the family of compounds of Formula (I) are thepharmaceutically-acceptable salts thereof. The term“pharmaceutically-acceptable salt” embraces salts commonly used to formalkali metal salts and to form addition salts of free acids or freebases. The nature of the salt is not critical, provided that it ispharmaceutically acceptable. Suitable pharmaceutically-acceptable acidaddition salts of compounds of Formula (I) may be prepared frominorganic acid or from an organic acid. Examples of such inorganic acidsare hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuricand phosphoric acid. Appropriate organic acids may be selected fromaliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic,carboxylic and sulfonic classes of organic acids, examples of which areformic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic,tartaric, citric, ascorbic, glucoronic, maleic, fumaric, pyruvic,aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic,p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethylsulfonic, benzenesulfonic, sulfanilic, stearic,cyclohexylaminosulfonic, algenic, galacturonic acid. Suitablepharmaceutically-acceptable base addition salts of compounds of Formula(I) include metallic salts made from aluminum, calcium, lithium,magnesium, potassium, sodium and zinc or organic salts made fromN,N′-dibenzylethyleneldiamine, choline, chloroprocaine, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procain. All of thesesalts may be prepared by conventional means from the correspondingcompound of Formula (I) by reacting, for example, the appropriate acidor base with the compound of Formula (I).

The present invention also comprises a pharmaceutical compositioncomprising a therapeutically-effective amount of a compound of Formulas(I) in association with at least one pharmaceutically-acceptablecarrier, adjuvant or diluent. Pharmaceutical compositions of the presentinvention can comprise the active compounds of Formula (I) inassociation with one or more non-toxic, pharmaceutically-acceptablecarriers and/or diluents and/or adjuvants (collectively referred toherein as “carrier” materials) and, if desired, other activeingredients. The active compounds of the present invention may beadministered by any suitable route, preferably in the form of apharmaceutical composition adapted to such a route, and in a doseeffective for the treatment intended.

The active compounds and composition may, for example, be administeredorally, intravascularly, intraperitoneally, subcutaneously,intramuscularly, oculary, or topically. For treating ocular build up offibrin, the compounds may be administered intraocularly or topically aswell as orally or parenterally.

The compounds can be administered in the form of a depot injection orimplant preparation which may be formulated in such a manner as topermit a sustained release of the active ingredient. The activeingredient can be compressed into pellets or small cylinders andimplanted subcutaneously or intramusculary as depot injections orimplants. Implants may employ inert materials such as biodegradablepolymers or synthetic silicones, for example, Silastic, silicone rubberor other silicon containing polymers.

The compounds can also be administered in the form of liposome deliverysystems, such as small unilamellar vesicles, large unilamellar vesiclesand multilamellar vesicles. Liposomes can be formed from a variety ofphospholipids, such as cholesterol, stearylamine orphosphatidylcholines.

The compounds may also be delivered by the use of monoclonal antibodiesas individual carriers to which the compound molecules are coupled. Thecompounds may also be coupled with soluble polymers as targetable drugcarriers. Such polymers can include polyvinylpyrrolidone, pyrancopolymer, polyhydroxy-propyl-methacrylamide-phenol,polyhydroxyethyl-aspartamide-phenol, or ployethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug, for example, polylactic acid, polyglycolicacid, copolymers of polylactic and polyglycolic acid, polyepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates and cross linked or amphitpathicblock copolymers of hydrogels.

For oral administration, the pharmaceutical composition may be in theform of, for example, tablets, capsules (each of which includessustained release or timed release formulations), pills, powders,granules, elixers, tinctures, suspensions, liquids including syrups, andemulsions. The pharmaceutical composition is preferably made in the formof a dosage unit containing a particular amount of the activeingredient. Examples of such dosage units are tablets or capsules. Theactive ingredient may also be administered by injection as a compositionwherein, for example, saline, dextrose or water may be used as asuitable carrier.

The amount of therapeutically active compounds which are administeredand the dosage regimen for treating a disease condition with thecompounds and/or compositions of this invention depends on a variety offactors, including the age, weight, sex and medical condition of thesubject, the severity of the disease, the route and frequency ofadministration, and the particular compound employed, and thus may varywidely.

The pharmaceutical compositions may contain active ingredients in therange of about 0.1 to 2000 mg, and preferably in the range of about 0.5to 500 mg. A daily dose of about 0.01 to 100 mg/kg body weight, andpreferably between about 0.5 and about 20 mg/kg body weight, may beappropriate. The daily dose can be administered in one to four doses perday.

The compounds may be formulated in topical ointment or cream, or as asuppository, containing the active ingredients in a total amount of, forexample, 0.075 to 30% w/w, preferably 0.2 to 20% w/w and most preferably0.4 to 15% w/w. When formulated in an ointment, the active ingredientsmay be employed with either paraffinic or a water-miscible ointmentbase.

Alternatively, the active ingredients may be formulated in a cream withan oil-in-water cream base. If desired, the aqueous phase of the creambase may include, for example at least 30% w/w of a polyhydric alcoholsuch as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol,polyethylene glycol and mixtures thereof. The topical formulation maydesirably include a compound which enhances absorption or penetration ofthe active ingredient through the skin or other affected areas. Examplesof such dermal penetration enhancers include dimethylsulfoxide andrelated analogs. The compounds of this invention can also beadministered by a transdermal device. Preferably topical administrationwill be accomplished using a patch either of the reservoir and porousmembrane type or of a solid matrix variety. In either case, the activeagent is delivered continuously from the reservoir or microcapsulesthrough a membrane into the active agent permeable adhesive, which is incontact with the skin or mucosa of the recipient. If the active agent isabsorbed through the skin, a controlled and predetermined flow of theactive agent is administered to the recipient. In the case ofmicrocapsules, the encapsulating agent may also function as themembrane.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier, it may comprise a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifiers) with orwithout stabilizer(s) make-up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include Tween 60, Span 80, cetostearyl alcohol,myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate,among others.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties, since the solubility of theactive compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as diisoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

For therapeutic purposes, the active compounds of the present inventionare ordinarily combined with one or more adjuvants appropriate to theindicated route of administration. If administered per os, the compoundsmay be admixed with lactose, sucrose, starch powder, cellulose esters ofalkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets maycontain a controlled-release formulation as may be provided in adispersion of active compound in hydroxypropylmethyl cellulose.Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules having one or more of the carriers or diluents mentioned foruse in the formulations for oral administration. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, and/or various buffers. Other adjuvants and modes ofadministration are well and widely known in the pharmaceutical art.

In practicing the methods of the present invention for the treatment andprevention of a variety of thrombotic conditions including coronaryartery and cerebrovascular disease, the compounds and pharmaceuticalcompositions of the present invention are administered alone or incombination with one another, or in combination with other therapeuticsor in vivo diagnostic agents. The coagulation cascade inhibitors of thepresent invention can also be co-administered with suitableanti-platelet agreggation agents, including, but not limited toticlopidine or clopidrogel, fibrinogen receptor antagonists (e.g. totreat or prevent unstable angina or to prevent reocculsion afterangioplasty and restenosis), anti-coagulants such as aspirin, warfarinor heparins, thrombolytic agents such as plasminogen activators orstreptokinase to achieve synergistic effects in the treatment of variouspathologies, lipid lowering agents including antihypercholesterolemics(e.g. HMG CoA reductase inhibitors such as mevastatin, lovastatin,simvastatin, pravastatin, and fluvastatin, HMG CoA synthataseinhibitors, etc.), anti-diabetic drugs, or other cardiovascular agents(loop diuretics, thiazide type diuretics, nitrates, aldosteroneantagonistics (i.e., spironolactone and epoxymexlerenone), angiotensinconverting enzyme (e.g. ACE) inhibitors, angiotensin II receptorantagonists, beta-blockers, antiarrythmics, anti-hypertension agents,and calcium channel blockers) to treat or prevent atheriosclerosis. Forexample, patients suffering from coronary artery disease, and patientssubjected to angioplasty procedures, would benefit from coadministrationof fibrinogen receptor antagonists and coagulation cascade inhibitors ofthe present invention. Also, coagulation cascade inhibitors couldenhance the efficiency of tissue plasminogen activator-mediatedthrombolytic reperfusion.

Typical doses of coagulation cascade inhibitors of the present inventionwith other suitable anti-platelet agents, anticoagulation agents,cardiovascular therapeutic agents, or thrombolytic agents may be thesame as those doses of coagulation cascade inhibitors administeredwithout coadministration of additional anti-platelet agents,anticoagulation agents, cardiovascular therapeutic agents, orthrombolytic agents, or may be substantially less than those doses ofcoagulation cascade inhibitors administered without coadministration ofadditional anti-platelet agents, anticoagulation agents, cardiovasculartherapeutic agents, or thrombolytic agents, depending on a patient'stherapeutic needs.

All mentioned references are incorporated by reference as if herewritten.

Although this invention has been described with respect to specificembodiments, the details of these embodiments are not to be construed aslimitations. The following examples are provided to illustrate thepresent invention and are not intended to limit the scope thereof.Without further elaboration, it is believed that one skilled in the artcan, using the preceding descriptions, utilize the present invention toits fullest extent. Therefore the following preferred specificembodiments are to be construed as merely illustrative and notlimitative of the remainder of the disclosure in any way whatsoever.Compounds containing multiple variations of the structural modificationsillustrated in the schemes or the following Examples are alsocontemplated. Those skilled in the art will readily understand thatknown variations of the conditions and processes of the followingpreparative procedures can be used to prepare these compounds.

One skilled in the art may use these generic methods to prepare thefollowing specific examples, which have been or may be properlycharacterized by ¹H NMR, mass spectrometry, elemental composition, andsimilar procedures. These compounds also may be formed in vivo. Thefollowing examples contain detailed descriptions of the methods ofpreparation of compounds of Formula (I). These detailed descriptionsfall within the scope and are presented for illustrative purposes onlyand are not intended as a restriction on the scope of the invention. Allparts are by weight and temperatures are Degrees centigrade unlessotherwise indicated.

The following general synthetic sequences are useful in making thepresent invention. Abbreviations used in the schemes and tables include:“AA” represents amino acids, “AcCN” represents acetonitrile, “AcOH”represents acetic acid, “BINAP” represents2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, “BnOH” represents benzylalcohol, “BnCHO” represents 2-phenylethanal, “BnSO₂Cl” representsbenzylsulfonyl chloride, “Boc” represents tert-butyloxycarbonyl, “BOP”represents benzotriazol-1-yl-oxy-tris(dimethylamino), “bu” representsbutyl, “dba” represents dibenzylidene-acetone, “DCC” represents1,3-dicyclohexylcarbodiimide, “DCM” represents dichloromethane ormethylene chloride, “DIBAH” or “DIBAL” represents diisobutylaluminumhydride, “DMF” represents dimethylformamide, “DMSO” representsdimethylsulfoxide, “DPPA” represents diphenylphosphoryl azide”, “EDC”represents 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride, “Ex. No.” represents Example Number, “Fmoc” represents9-fluorenylmethoxycarbonyl, “HOBt” represents hydroxybenzoltriazole”,“LDA” represents lithium diisopropylamide, “MW” represents molecularweight, “NMM” represents N-methylmorpholine, “Ph” represents phenyl oraryl, “PHTH” represents a phthaloyl group, “pnZ” represents4-nitrobenzyloxycarbonyl, “PTC” represents a phase transfer catalyst,“py” represents pyridine, “RNH₂” represents a primary organic amine,“SEM” represents 2-(trimethylsilyl)ethoxy-methyl chloride, “p-TsOH”represents paratoluenesulfonic acid, “TBAF” representstetrabutylammonium fluoride, “TBTU” represents2-(1H-benzotriozole-1-yl)-1,1,3,3-tetramethyl uronium tetrafluoroborate,“TEA” represents triethylamine, “TFA” represents trifluoroacetic acid,“THF” represents tetrahydrofuran, “TMS” represents trimethylsilyl,“TMSCN” represents trimethylsilyl cyanide, and “Cbz” or “Z” representsbenzyloxycarbonyl.

GENERAL SYNTHETIC PROCEDURES AND SPECIFIC EXAMPLES

The compounds of the present invention can be synthesized, for example,according to the following procedures and Schemes given below.

A general synthetic approach to a wide variety of R²-substitutedpyrimidinones is shown in Schemes 1 through Scheme 5 below. Treatment ofa solution of ethyl benzinidate hydrochloride in methanol withaminoacetaldehyde dimethyl acetal provided the substituted benzamidine.Cyclization of the benzamidine with dimethyl methoxymethylene-malonateresulted in the formation of the pyrimidinone heterocyclic core with therequired functional groups for further manipulation. Demethylation ofthe ester with lithium iodide followed by Curtius rearrangement of theresulting acid installed the crucial nitrogen at C-5 as a protectedcarbamate. Hydrolysis of the dimethyl acetal and oxidation of theresulting aldehyde with sodium chlorite gave the glycine unit at N-3.Protection of the acid as a t-butyl ester followed by deprotection ofcarbamate by hydrogenation gave the free amine at C-5. Treatment of thisamine with a sulfonyl chloride or with an aldehyde under reductiveamination conditions gave the sulfonamide or secondary amine,respectively. The protected acids were then unmasked with HCl. Theseacids are then coupled under standard peptide coupling conditions withvarious amines. These amines are typically multifunctional, and are usedin some protected form. Removal of these protecting groups provides thecompounds for evaluation. These synthetic schemes and procedures areexemplified below.

Synthesis Scheme 1 through Scheme 5 are exemplified in the followingexamples.

Example 1

(EX-1A) A solution of ethyl benzimidate hydrochloride (92.25 g, 496.9mmol) in 300.0 mL dry methanol (1.68 M) was cooled to ca 0° C. and addeda solution of aminoacetaldehyde dimethyl acetal (73.10 mL, 670.9 mmol)in dry methanol (75.0 mL, 9.0 M) drop wise at such a rate thetemperature was kept below 5° C. The resulting solution was allowed tostir for 3 days with the temperature being maintained below 5° C. Thereaction mixture was then concentrated under reduced pressure to give ayellow oil. The residue was dissolved in 1 N NaOH (750 mL) and extractedwith dichloromethane (4×250 mL). The organic solutions were combined,dried (MgSO₄), and concentrated to give 108.13 g crudeN-(2,2-dimethoxyethyl)benzamidine as a yellow oil. The crudeN-(2,2-dimethoxyethyl)benzamidine (108.13 g, 519.2 mmol) in dry methanol(125.0 mL, 4.2 M) was added dimethyl methoxymethylenemalonate (94.13 g,540.5 mmol) in one portion at room temperature. The resulting mixturewas heated to approximately 100° C., where the solvent was slowlydistilled off over a two hour period. The resulting dark brown solutionwas allowed to cool to room temperature and was diluted ethyl acetate (1L). The organic solution was washed with saturated NH₄Cl (2×500 mL) andbrine 1×500 ml). The organic solution was dried (MgSO₄), filtered andconcentrated. Purification of the crude product by MPLC (25% ethylacetate/hexane) gave pure methyl1-(2,2-dimethoxyethyl-2-phenylpyrimidin-6(1H)-one-5-carboxylate (EX-1A)in 73% yield as a tan oil: ¹H NMR (300 MHz, CDCl₃) δ 8.73 (s, 1H),7.59-7.49 (m, 5H), 4.86 (t, J=5.5 Hz, 1H), 4.16 (d, J=5.4 Hz, 2H), 3.95(s, 3H), 3.32 (s, 6H); ¹³CNMR (75 Hz, CDCl₃) δ 165.9, 164.6, 159.3,158.2, 134.6, 130.9, 128.93, 128.78, 114.9, 101.4, 56.0, 55.1, 52.7,49.1; HRMS (ES) calcd for C₁₆H₁₉N₂O₅ 319.1294, found 319.1288.

(EX-1B) A solution of methyl1-(2,2-dimethoxyethyl-2-phenylpyrimidin-6(1H)-one-5-carboxylate (93.00g, 292.2 mmol) in 420.0 mL dry pyridine (0.70 M) was added lithiumiodide (98.00 mL, 732.2 mmol) in one portion with stirring at roomtemperature, upon which an exotherm occurs. The resulting light brownsuspension was heated to reflux for 2 hours. The dark brown reaction wasallowed to cool to room temperature and the volatiles were removed underreduced pressure. The resulting oil was diluted with 1 N HCl (500 mL).The aqueous solution was extracted with dichloromethane/methanol (4:1,4×250 mL). The combined organic solutions were washed with 6 N HCl(2×250 mL), dried (MgSO₄), filtered and concentrated. The crude productwas purified by crystallization (ethyl acetate/hexane) to give pure1-(2,2-dimethoxyethyl-2-phenylpyrimidin-6(1H)-one-5-carboxylate (EX-1B)in 63% yield as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 12.99 (s, 1H),8.97 (s, 1H), 7.63-7.51 (m, 5H), 4.78 (dd, J=4.3, 5.5 Hz, 1H), 4.28 (d,J=5.4 Hz, 2H), 3.30 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 165.8, 165.1,164.1, 159.1, 133.6, 131.5, 129.1, 129.0, 112.6, 101.0, 55.8, 49.2; HRMS(ES) calcd for C₁₅H₁₇N₂O₅ 305.1137, found 305.1113.

(EX-1C) A suspension of1-(2,2-dimethoxyethyl-2-phenylpyrimidin-6(1H)-one-5-carboxylate (65.93g, 216.67 mmol) in 800 mL 1,4-dioxane (0.27 M) was added triethylamine(50.0 mL, 358.7 mmol) followed by diphenylphosphoryl azide (51.40 mL,238.5 mmol) in one portion at room temperature. The resulting solutionwas slowly heated to reflux for 2 hours. The reaction mixture was thenadded benzyl alcohol (45.00 mL, 434.8 mmol) and refluxing was maintainedfor approximately 14 hours. The black solution was allowed to cool toroom temperature, and the volatiles were removed under vacuum. Theresulting residue was diluted with ethyl acetate (1.5 L). The organicsolution was washed with saturated NH₄Cl (2×500 mL), 1 N NaOH 1×500 mL),and brine 1×500 ml). The organic solution was dried (MgSO₄), filteredand concentrated to give the crude product. Purification by MPLC(15%-30%ethyl acetate/hexane) afforded pure[5-[(benzyloxycarbonyl)amino]-2-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl]acetaldehydedimethyl acetal (EX-1C) as light brown solid in 46% yield: ¹H NMR (400MHz, CDCl₃) δ 8.72 (br s, 1H), 7.53-7.32 (m, 11H), 5.20 (s, 2H), 4.68(t, J=5.6 Hz, 1H), 4.12 (d, J=5.6 Hz, 2H), 3.22 (s, 6H); “¹³C NMR (100MHz, CDCl₃) δ 158.3, 153.7, 153.2, 135.9, 134.9, 134.7, 130.1, 129.1,128.9, 128.8, 128.71, 128.66, 128.4, 125.1, 101.3, 67.7, 55.4,48.6; HRMS(EI) calcd for C₂₂H₂₄N₃O₅ 410.1716, found 410.1741.

(EX-1D) A solution of[5-[(benzyloxycarbonyl)amino]-2-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl]acetaldehydedimethyl acetal (17.24 g, 42.11 mmol) in 103.0 mL tetrahydrofuran wasadded 35.0 mL 1 N HCl. The resulting biphasic mixture was allowed toheated to reflux for 12 hours. The reaction mixture was allowed to coolto room temperature and the volatiles were removed under vacuum. Theresulting residue was diluted.with water (200 mL) and the pH wasadjusted to 7 by addition of solid NaHCO3. The resulting emulsion wasextracted with dichloromethane (4×150 mL). The combined organicsolutions were washed with water 1×200 mL), dried (MgSO₄), filtered, andconcentrated to give 15.74 g crude[5-[(benzyloxycarbonyl)amino]-2-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl]acetaldehyde.

A solution of crude[5-[(benzyloxycarbonyl)amino]-2-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl]acetaldehyde(15.30 g, 42.11 mmol) in 198.0 mL of tetrahydrofuran, t-butyl alcohol,and 2-methyl-2-butene (1:1:1.3, 0.21 M) was cooled to 0° C. The solutionwas then slowly added a solution of sodium chlorite (29.94 g, 331.1mmol) and sodium dihydrogenphosphate monohydrate (35.42 g, 256.7 mmol)in 102.0 mL of water (3.2 M based on sodium chlorite). The resultinggold colored, biphasic solution was stirred for 10 minutes and the coldbath was removed. The reaction was stirred for 1 hour at roomtemperature. The volatiles were removed under reduced pressure. Theresulting solution was diluted with water (200 mL) and the pH wasadjusted to 3 by addition of sat NaHCO3 and 1 N HCl. The aqueoussolution was extracted by tetrahydrofuran, dichloromethane (1:2, 4×180mL). The combined organic solutions were dried (MgSO4), filtered, andconcentrated to give the crude product. Purification by trituration withethyl ether gave an 88% yield of[5-[(benzyloxycarbonyl)amino]-2-phenyl-6-oxo-1,6-dihydro1-pyrimidinyl]acetic acid as a white solid: ¹H NMR (300 MHz, d-DMSO) δ13.34 (br s, 1H), 9.03 (s, 1H), 7.57-7.34 (m, 10H), 5.23 (s, 2H), 4.56(s, 2H); ¹³C NMR (75 MHz, d-DMSO) δ 169.4, 158.0, 154.6, 154.3, 137.1,134.8, 130.9, 129.4, 129.1, 128.78, 128.72, 128.50, 125.5, 67.0, 48.8;HRMS (EI) calcd for C₂₀H₁₈N₃O₅ 380.1246, found 380.1246.

(EX-1E) A suspension of[5-[(benzyloxycarbonyl)amino]-2-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl]aceticacid (5.2503 g, 13.84 mmol) in 70.0 mL chloroform (0.2 M) was cooled inan ice bath to approximately 0° C. The cold suspension was then addedoxalyl chloride (6.00 mL, 68.78 mmol) drop wise via syringe. Aftervigorous gas evolution, a golden homogeneous solution resulted. Afterstirring for 5 minutes, the cold bath was removed and the solution wasstirred for an additional 2 hours at room temperature. The solvent wasremoved under reduced pressure and placed on the high vacuum system toremove residual solvents for 10 minutes. The resulting yellow solid wasdiluted with 70.0 mL chloroform (0.2 M) and added pyridine (1.70 mL,21.02 mmol) and 2-methyl-2-propanol (3.50 ml, 36.60 mmol). The resultingtan colored solution was stirred for 1 hour at room temperature, andthen heated to reflux for 12 hours. The reaction mixture was cooled toroom temperature and diluted with chloroform (300 mL). The organicsolution was washed with water (1×100 mL), saturated NaHCO₃ (1×100 mL),and brine (1×100 mL). The organic solution was dried (MgSO₄), filteredand concentrated. The crude reaction was purified by MPLC (25% ethylacetate/hexanes) to give the product in 49% yield: ¹H NMR (300 MHz,CDCl₃) δ 8.81 (br s, 1H), 7.57-7.38 (m, 1 1H), 5.27 (s, 2H), 4.57 (s,2H), 1.47 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 166.4, 158.0, 153.2, 135.9,135.0, 134.4, 130.6, 129.1, 128.9, 128.7, 128.5, 128.4, 125.4, 83.4,67.7, 49.1, 28.2; HRMS (EI) calcd for C₂₄H₂₆N₃O₅ 436.1872, found436.1876.

(EX-1F) A solution of[5-amino-2-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl]acetic acid t-butylester (1.8647 g, 4.282 mmol) in 21.0 mL methanol (0.2 M) was added 2113mg 10% Pd/C in one portion. The resulting mixture was stirred under anatmosphere of hydrogen gas (balloon) at room temperature forapproximately 16 hours. The crude reaction mixture was filtered througha pad of Celite 545 and the solvent was removed under reduced pressure.The crude product was triturated from ethyl ether to give pure product[5-amino-2-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl]acetic acid t-butylester (EX-1F) in 99% yield: ¹H NMR (400 MHz, CDCl₃) δ 7.41-7.39 (m, 6H),4.48 (s, 2H), 4.06 (br s, 2H), 1.39 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ166.8, 158.6, 149.3, 134.9, 132.9, 130.0, 128.9, 128.5, 127.7, 82.9,48.7, 28.1; HRMS (EI) calcd for C₁₆H₂₀N₃O₃ 302.1505, found 302.1491.

(EX-1G) A solution of[5-amino-2-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyljacetic acid t-butylester (1.0300 g, 3.418 mmol) in 5.5 mL tetrahydrofuran and 2.0 mLdimethylformamide (0.45 M) was added N-methylmorpholine (1.20 mL, 10.91mmol) in one portion. The solution was cooled to 0° C. in an ice bath.After stirring for 10 minutes, a solution of 718.2 mg a-toluenesulfonylchloride (3.767 mmol) in 5.5 niL tetrahydrofuran (0.68 M) was added dropwise over a 5 minute period. The reaction mixture was stirred for 2hours at 0° C. The reaction mixture was diluted with ethyl acetate (150mL). The organic solution was washed with 1 N HCl (2×25 mL), saturatedNaHCO₃ (2×25 mL), and brine 1×50 mL). The organic solution was dried(MgSO₄), filtered and concentrated under reduced pressure. The resultingyellow solid was triturated with ethyl ether, filtered, and dried undervacuum to afford pure product (EX-1G) as a white solid in 74% yield: ¹HNMR (400 MHz, d-DMSO) δ 9.34 (s, 1H), 7.76 (s, 1H), 7.55-7.28 (m, 10H),4.59 (s, 2H), 4.49 (s, 2H), 1.32 (s, 9H); ¹³C NMR (100 MHz, d-DMSO) δ167.0, 158.8, 156.5, 142.1, 134.5, 131.7, 131.0, 130.1, 129.4, 129.0,128.94, 128.58, 124.8, 83.0, 59.6, 49.2, 28.1; HRMS (EI) calcd forC₂₃H₂₆N₃O₅S 456.1593, found 456.1597.

(EX-1H) A solution of (EX-1G) (1.0643 g, 2.336 mmol) in 9.0 mL 4M HCl indioxane (0.1 M) was stirred for 12 hours at room temperature. The crudereaction was concentrated under reduced pressure. The resulting residuewas triturated with ethyl ether to afford pure product (EX-1H) in 87%yield as a white solid: ¹H NMR (400 MHz, d-DMSO) δ 9.32 (s, 1H), 7.74(s, 1H), 7.51-7.30 (m, 10H), 4.58 (s, 2H), 4.48 (s, 2H); ¹³C NMR (100MHz, d-DMSO) δ 169.2, 158.7, 156.6, 141.9, 134.5, 131.7, 131.0, 130.1,129.4, 129.0, 128.90, 128.56, 124.8, 59.6,48.9; HRMS (EI) calcd forC₁₉H₁₈N₃O₅S 400.0967, found 400.0959.

(EX-1I) A solution of acid (EX-1H) (406.8 mg, 1.018 mmol) in 10.0 mLdimethylformamide (0.10 M) was added N,N-diisopropylethylamine (0.900mL, 5.167 mmol), N-hydroxybenzotriazole (167.7 mg, 1.241 mmol), and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (236.1 mg,1.232 mmol). The resulting mixture was allowed to stir for 30 minutes atroom temperature after which the mixture had become homogeneous. Thereaction mixture was then added 4-(Cbz-amidino)benzylamine (324.6 mg,1.126 mmol) in one portion at room temperature. The resulting mixturewas then allowed to stir for 18 hours. The reaction mixture was dilutedwith ethyl acetate (50 mL). The organic solution was washed with 5%citric acid (1×25 mL), saturated NaHCO₃ (1×25 mL), and brine (1×25 mL).The organic solution was dried (MgSO₄), filtered and concentrated. Thecrude reaction mixture was purified trituration with ethyl ether toafford pure product (EX-1I) in as a white solid: ¹H NMR (300 MHz,d-DMSO) δ 9.36-9.18 (br m, 3H), 8.82-8.78 (m, 1H), 7.98 (d, J=8.3 Hz,2H), 7.84, (s, 1H), 7.56-7.32 (m, 16H), 5.15 (s, 2H), 4.65 (s, 2H), 4.58(s, 2H), 4.40 (d, J=5.4 Hz, 2H); HRMS (EI) calcd for C₃₅H₃₃N₆O₆S₂665.2182, found 665.2177.

A solution of Cbz-amidine (EX-1I) (237.7 mg, 357.6 mmol) in 3.5 mLmethanol and 4 M HCl in dioxane (4:1, 0.1 M) was added 42.1 mg 10% Pd/Cin one portion. The resulting mixture was stirred under an atmosphere ofhydrogen gas (balloon) at room temperature for approximately 16 hours.The crude reaction mixture was filtered through a pad of Celite 545 andthe solvent was removed under reduced pressure. Purification of thecrude product by HPLC (gradient, 5%-95% acetonitrile/water with 0.1%trifluoroacetic acid) afforded pure product as a white solid: ¹H NMR(300 MHz, d-DMSO) δ 9.31-9.28 (m, 4H), 8.88 (br s, 1H), 7.81-7.77 (m,3H), 7.60-7.54 (m, 5H), 7.43-7.37 (m, 7H), 4.65 (s, 2H), 4.58 (s, 2H),4.42-4.41 (m, 2H); HRMS (EI) calcd for C₂₇H₂₇O₄S 531.1815, found531.1794.

Example 2

By following the method of Example 1, the title compound was prepared:¹H NMR (300 MHz, d-DMSO) δ 9.40-9.33 (m, 4H), 8.86 (s, 1H), 7.82 (s,2H), 7.72-7.37 (m, 15H), 4.65-4.59 (m, 4H), 4.41-4.40 (m, 2H); HRMS (EI)calcd for C₂₇H₂₇N₆O₄S 531.1815, found 531.1794.

Example 3

(EX-3A) A solution of[5-amino-2-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl]acetic acid t-butylester (EX-1F) (613.7 mg, 2.037 mmol) in 7.0 mL tetrahydrofuran anddichioromethane (1:1, 03 M) was added 25.0 mL acetic acid andphenylacetaldehyde (0.475 mL, 4.060 mmol). The solution was cooled to 0°C. in an ice bath and added sodium triacetoxyborohydride (1.9131 g,9.027 mmol) in one portion. After stirring for 5 minutes, the ice bathwas removed and the reaction mixture was allowed to stir at roomtemperature for 2 hours. The reaction was quenched by the addition of 1N NaOH (5 mL), and the mixture was stirred for 5 minutes. The reactionmixture was diluted 0.5 N NaOH (100 mL). The aqueous solution wasextracted with ethyl acetate (3×25 mL). The combined organic solutionswere washed with 0.5 N NaOH (1×25 mL) and brine (1×25 mL). The solutionwas dried (MgSO₄), filtered and concentrated under reduced pressure.Purification by MPLC (25% ethyl acetate/hexanes) afforded EX-3A as ayellow oil in 74% yield: ¹H NMR (400 MHz, CDCl₃) δ 7.43-7.40 (m, 4H),7.31-7.26 (m, 2H), 7.23-7.16 (m, 5H), 4.70 (br s, 1H), 4.49 (s, 2H),3.38-3.34 (m, 2H), 2.96-2.92 (m, 2H), 1.40 (s, 9H); HRMS (EI) calcd forC₂₄H₂₈N₃O₃ 406.2131, found 406.2125.

A solution of EX-3A (521.3 mg, 1.286 mmol) in 13.0 mL 4M HCl in dioxane(0.1 M) was stirred for 12 hours at room temperature. The crude reactionwas concentrated under reduced pressure. The resulting residue wastriturated with ethyl ether to afford pure product EX-3B in quantitativeyield as a yellow solid: ¹H NMR (300 MHz, d-DMSO) δ 7.66-7.57 (m, 5H),7.33-7.23 (m, 6H), 4.57 (s, 2H), 3.443.35 (m, 2H), 2.97-2.92 (m, 2H);¹³C NMR (75 MHz, d-DMSO) δ 168.8, 157.0, 148.0, 139.9, 135.0, 132.2,129.69, 129.48, 129.07, 126.9, 48.8, 44.5, 34.5; HRMS (EI) calcd forC₂₀H₂₀N₃O₃ 350.1505, found 350.1520.

A solution of EX-3B (497.8 mg, 1.290 mmol) in 13.0 mL dimethylformamide(0.10 M) was added N,N-diisopropylethylamine (1.800 mL, 10.33 mmol),N-hydroxybenzotriazole (212.8 mg, 1.575 mmol), and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (302.5 mg,1.578 mmol). The resulting mixture was allowed to stir for 30 minutes atroom temperature after which the mixture had become homogeneous. Thereaction mixture was then added 4-(Cbz-amidino)benzylamine (410.9 mg,1.425 mmol) in one portion at room temperature. The resulting mixturewas then allowed to stir for 18 hours. The reaction mixture was dilutedwith ethyl acetate (50 mL). The organic solution was washed with 5%citric acid (1×25 ML), saturated NaHCO₃ (1×25 mL), and brine (1×25 mL).The organic solution was dried (MgSO₄), filtered and concentrated. Thecrude reaction mixture was purified trituration with ethyl ether toafford pure product EX-3C in as a white solid: ¹H NMR (400 MHz, d-DMSO)δ 9.08 (br s, 2H), 8.62 (t, J=5.8 Hz, 1H), 7.90 (d, J=8.3 Hz, 2H),7.44-7.15 (m, 17H), 5.35 (t, J=5.9 Hz, 1H), 5.07 (s, 2H), 4.44 (s, 2H),4.29 (d, J=5.4 Hz, 2H), 3.31-3.26 (m, 2H), 2.88-2.85 (m, 2H); HRMS (EI)calcd for C₃₆H₃₅N₆O₄ 615.2720, found 615.2688.

A solution of EX-3C (222.6 mg, 362.1 mmol) in 4.0 mL methanol and 4 MHCl in dioxane (3:1, 0.1 M) was added 53.0 mg 10% Pd/C in one portion.The resulting mixture was stirred under an atmosphere of hydrogen gas(balloon) at room temperature for approximately 16 hours. The crudereaction mixture was filtered through a pad of Celite 545 and thesolvent was removed under reduced pressure. Purification of the crudeproduct by trituration from ethyl ether afforded pure product as ayellow solid: ¹H NMR (300 MHz, d-DMSO) δ 9.62-9.30 (br m, 5H), 7.88 (brm, 2H), 7.58-6.86 (br m, 15H), 4.59 (br s, 2H), 4.36 (br s, 2H), 3.38(br s, 2H), 2.91 (br s, 2H); HRMS (EI) calcd for C₂₈H₂₉N₆O₂ 481.2352,found 481.2348.

Pyrimidinones having, for example, a directly bonded 2-aryl,2-heteroaryl, or 2-heteroatom linking/bonding an organic group throughthe heteroatom to the pyrimidinone ring can be prepared using Scheme 6and Scheme 7 below. The heteroatom is typically a sulfur, nitrogen,oxygen, or another suitable heteroatom. Use of the general procedure inScheme 6 to prepare specific heteroatom substituted pyrimidinones isdisclosed in Examples 4 and 5.

Example 4

(EX-4A) A solution of 5-nitro-2,4(1H,3H) pyrimidinedione indimethylsulfoxide (0.2 M) is added 1.1 equivalents potassium carbonatein one portion with stirring. After approximately 10 minutes, a solutionof 1 equivalent 2-(trimethylsilyl)ethoxy-methyl chloride indimethylsulfoxide is added drop wise. The reaction mixture is thenheated to 40° C. and allowed to stir for 18 hours. Typical aqueous workup followed by chromatographic purification provides pure product EX-4A.

EX-4B) A solution of 5-nitro-1-SEM-2,4(1H,3H) pyrimidinedione (EX-4A) indimethylsulfoxide (0.2 M) is added 1.1 equivalents potassium carbonatein one portion with stirring. After approximately 10 minutes a solutionof I equivalent methyl bromoacetate in dimethylsulfoxide is added dropwise. The reaction mixture is then heated to 40° C. and allowed to stirfor 18 hours. Typical aqueous work up followed by chromatographicpurification provides pure product EX-4B.

EX-4C) A solution of 5-nitro-1-SEM-3-methoxycarbonylmethyl (EX-4B)2,4(1H,3H)pyrimidinedione in methanol is degassed with hydrogen gas. Tothe solution is then added 5% Pd/C which is stirred under an atmosphereof hydrogen at room temperature for 24 hours. The crude reaction isfiltered through a pad of Celite 545 and concentrated under reducedpressure. Purification by column chromatography gives pure5-amino-1-SEM-3-methoxycarbonylmethyl-2,4(1H,3H)pyrimidinedione EX-4C.

EX-4D) To a solution of5-amino-1-SEM-3-methoxycarbonylmethyl-2,4(1H,3H)pyrimidinedione (EX-4C)in tetrahydrofuran and dichloromethane (1:1, 0.3 M) is added a catalyticamount of acetic acid and 1 equivalent phenylacetaldehyde. The solutionis cooled to 0° C. in an ice bath and 1 equivalent sodiumtriacetoxyborohydride is added in one portion. After stirring for 5minutes, the ice bath is removed, and the reaction mixture is allowed tostir at room temperature for 2 hours. The reaction is quenched by theaddition of 1 N NaOH, and the mixture is stirred for 5 minutes. Typicalaqueous work up, followed by chromatographic purification provides pureproduct EX-4D.

EX-4E) To a solution of1-SEM-3-methoxycarbonylmethyl-5-(2-phenylethyl)amino-2,4(1H,3H)pyrimidinedione(EX-4D) in tetrahydrofuran and methanol (1:1, 0.2 M) is added 1equivalent of lithium hydroxide in water. After the reaction iscomplete, the volatiles are removed under reduced pressure. Theremaining aqueous solution is cooled in an ice bath and acidified to apH of 1 with 1.0 N HCl. Extraction with organic solvent and removal ofthe solvent under reduced pressure gives pure product EX-4E.

EX-4F) To a solution of1-SEM-3-methylenecarboxy-5-(2-phenylethyl)amino-2,4(1H,3H)pyrimidinedionedimethylformamide (0.1 M) are added 5 equivalents ofN,N-diisopropylethylamine, 1 equivalent of N-hydroxybenzotriazole, and 1equivalent of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride. The resulting mixture is stirred for 30 minutes. Thereaction mixture is then treated with 1 equivalent of the appropriateamine and allowed to stir over night. Typical aqueous work up followedby chromatographic purification gives pure product EX-4F.

EX-4G) To a solution of1-SEM-3-methylenecarbamide-5-(2-phenylethyl)amino-2,4(1H,3H)pyrimidinedionein tetrahydrofuran (0.3M) is added 2 equivalents of tetrabutylammoniumfluoride in tetrahydrofuran. The resulting solution is refluxed forseveral hours. Typical aqueous work up is followed by chromatographicpurification to give pure product EX-4G.

EX-4H) To a solution of3-methylenecarboxamide-5-(2-phenylethyl)amino-2,4(1H,3H)pyrimidinedione(EX-4G) in N,N-dimethylaniline (0.3M) is added 1 equivalent ofphosphorus oxychloride. The resulting solution is refluxed for severalhours. Typical aqueous work up is followed by chromatographicpurification to give pure product EX-4H.

EX-4I) To a solution of2-chloro-3-methylenecarboxamide-5-(2-phenylethyl)amino-2,4(1H,3H)pyrimidinedione(EX-4H) in dioxane (0.3M) is added 2 equivalents of phenylthiol. Theresulting solution is refluxed for several hours. Typical aqueous workup is followed by chromatographic purification to give pure productEX-4I.

A solution of2-thiophenyl-3-methylenecarboxamide-5-(2-phenylethyl)amino-2,4(1H,3H)pyrimidinedione(EX-4I) in methanol and 4M HCl dioxane (3:1, 0.1 M) is degassed withhydrogen gas. To the solution is then added 5% Pd/C which is stirredunder an atmosphere of hydrogen at room temperature for 24 hours. Thecrude reaction is filtered through a pad of Celite 545 and concentratedunder reduced pressure. Purification by column chromatography gives pureproduct.

Example 5

EX-5A) To a degassed solution of2-chloro-3-methylenecarboxamide-5-(2-phenylethyl)amino-2,4(1H,3H)pyrimidinedioneand 1 equivalent of 3-pyridineboronic acid in 1-propanol (0.5M) is added1.2 equivalents of 2.0 M sodium carbonate followed by 1 mol % oftetrakis(triphenylphosphine)palladium. The resulting mixture is heatedto reflux for several hours. After cooling to room temperature, typicalaqueous work up is followed by chromatographic purification to give pureproduct EX-5A.

A solution of2-(3-pyridinyl)-3-methylenecarboxamide-5-(2-phenylethyl)amino-2,4(1H,3H)pyrimidinedione(EX-5A) in methanol and 4M HCl dioxane (3:1, 0.1 M) is degassed withhydrogen gas. To the solution is then added 5% Pd/C, and the solution isstirred under an atmosphere of hydrogen at room temperature for 24hours. The crude reaction is filtered through a pad of Celite 545 andconcentrated under reduced pressure. Purification by columnchromatography gives pure product.

Pyrimidinones having, for example, a directly bonded 2-aryl,2-heteroaryl, or 2-heteroatom linking/bonding an organic group throughthe heteroatom to the pyrimidinone ring can also be prepared usingScheme 7 below. In this reaction scheme, the aryl is introduced byforming a carbon-carbon bond. Heteroatom suitable for formingheterolinked aryl pyrimidinones include sulfur, nitrogen, oxygen, oranother suitable heteroatom. Use of the general procedure in Scheme 7 toprepare specific heteroatom substituted pyrimidinones is disclosed inExamples 6 and 7.

Example 6

(EX-6A) 2-Thiouracil (66.7 g, 520.5 mmol) was dissolved in a sodiumhydroxide solution (41.6 g of solid NaOH in 365 mL of water). Themixture was then treated with methyl iodide (37 mL, 583 mmol), and theresulting reaction mixture was allowed to stir for 16 h at roomtemperature. The solution was then acidified with glacial acetic acid(30 mL). The white precipitate was collected by suction filtration, andthe solid was washed several times with cold water and dried to afford74 g of EX-6A as a white crystalline solid in quantitative yield.

(EX-6B) A solution of EX-6A (74.0 g, 520.5 mmol) in glacial acetic acid(2275 mL) was cooled to 0° C. with an ice bath and treated with Br₂. Thereaction mixture was allowed to warm to room temperature, and to stirfor 16 h. A yellow precipitate formed which was filtered and washed withether three times. 97.2 g of EX-6B was isolated in 62% yield.

(EX-6C) A mixture of calcium hydride in THF was cooled to 0° C. andtreated with neat EX-6B followed by neat t-butyl bromoacetate. Thereaction mixture was allowed to stir at 0° C. for 1 h. The reactionmixture was then allowed to stir for 2 h after the mixture was allowedto warm to room temperature. The reaction mixture was heated to refluxtemperature for 16 h. After the reaction mixture was cooled to roomtemperature, the mixture was slowly poured into a 1 L ice water slurry.The quenched mixture was extracted with dichloromethane (3×500 mL). Theorganic layers were combined and washed with water and brine. After theorganic layer was dried over MgSO₄ and filtered, the volatile componentswere removed in vacuo to afford 28.81 g (90%) of EX-6C as an off whitesolid as a mixture of N-alkylated and 0-alkylated isomers (9:1).N-alkylated isomer ¹H NMR (300 MHz, CDCl₃) d 8.07 (s, 1H), 4.75 (s, 2H),2.57 (s, 3H), 1.47 (s, 9H); ¹³ C NMR (75 MHz, CDCl₃) d 165.1, 162.7,158.4, 152.5, 108.3, 83.7, 46.8, 28.2 (3C), 15.5; HRMS (EI) calcd forC₁₁H₁₅BrN₂O₃S 335.0065, found 335.0077.

(EX-6D) In an argon-filled glove box a 12 ounce Fischer-Porter bottlecontaining a magnetic stir bar was charged with EX-6C (5.00 g, 15.0mmol), Pd(OAc)₂ (168 mg, 0.75 mmol, 5 mole %), rac-BINAP (654 mg, 1.05mmol, 7 mole %), Cs₂CO₃ (6.84 g, 21.0 mmol), and anhydrous, degassedtoluene (65.0 ml). To this mixture was added isopropyl amine (3.00 ml,35.2 mmol). The bottle was capped with a pressure head fitted with apressure gauge and removed from the glove box. The closed-system washeated in an oil bath at 118-120° C. with magnetic stirring for 16 hthereafter. A head-space pressure of 10 psi was developed during thereaction. The Fischer-Porter bottle containing the reaction mixture wasremoved from the oil bath, allowed to cool for 30 min, vented to anargon-flow system and sampled by syringe. LCMS analysis showed 35%product with 65% starting material remaining. Under a blanket of argon,the pressure head was removed and the reaction mixture was treated withPd(OAc)₂ (337 mg, 1.5 mmol, 10 mole %), rac-BINAP (1.00 g, 1.6 mmol, 11mole %), Cs₂CO₃ (10.0 g, 30.7 mmol), and isopropyl amine (6.00 ml, 70.4mmol). The bottle was capped with the pressure head and again heated to118-120° C. with magnetic stirring for 16 h. The sampling procedure wasrepeated and LCMS revealed that the reaction was complete. The reactionmixture was allowed to cool to RT and filtered through a medium fritsintered-glass funnel. The solids were washed thoroughly with tolueneand discarded. The filtrate was concentrated and purified by flashchromatography (Merck 230-400 mesh SiO₂, 10% ethyl acetate in hexanes)to afford 3.80 g (81% yield) of (EX-6D) as a tan solid: ¹H NMR (300 MHz,CDCl₃) d 7.05 (s, 1H), 4.74 (s, 2H), 3.44 (septet, J=6.3 Hz, 1H), 2.53(s, 3H), 1.47 (s, 9H), 1.21 (d, J=6.3 Hz, 6H); ¹³C NMR (75 MHz, CDCl₃) d165.7 (s), 158.7 (s), 147.4 (s), 130.5 (s), 123.6 (d), 82.9 (s), 45.9(t), 44.1 (d), 28.0 (q), 22.1 (q), 14.8 (q); HRMS (ESI) calcd forC₁₄H₂₄N₃SO₃ [M+H]⁺=314.1538, found 314.1539.

(EX-6E) In an argon-filled glove box a 3 ounce Fischer-Porter bottlecontaining a magnetic stir bar was charged with EX-6D (1.00 g, 3.20mmol), 3-nitrophenyl boronic acid (634 mg, 3.80 mmol),Cu(I)-2-thiophenecarboxylate (1.21 g, 6.37 mmol), and Pd(PPh3)₄ (100 mg,0.86 mmol, 2.7 mol %). THF (25 ml) was added and the bottle was cappedwith a pressure head fitted with a pressure gauge and removed from theglove box. The closed-system was heated in an oil bath at 70° C. withmagnetic stirring for 16 h thereafter. The reaction mixture was allowedto cool to RT, vented and diluted with ether (200 ml). The mixture wasfiltered through a medium frit sintered glass funnel. The green solidwas washed with ether (100 ml) and discarded. The filtrate wasconcentrated and purified by flash chromatography (Merck 230-400 meshSiO₂, 10% ethyl acetate in hexanes to 30%) to afford 961 mg (78% yield)of EX-6E as a yellow foam: ¹H NMR (300 MHz, CDCl₃) d 8.39 (s, 1H), 8.31(d, J=8.1 Hz, 1H), 7.86 (d, J=7.8 Hz, 1H), 7.64 (t, J=8.1 Hz, 1H), 7.15(bs, 1H), 4.51 (s, 2H), 3.58 (septet, J=6.0 Hz, 1H), 1.46 (s, 9H), 1.27(d, J=6.3 Hz, 6H); HRMS (ESI) calcd for C₁₉H₂₅N₄O₅ [M+H]⁺=389.1815,found 389.1825.

(EX-6F) A 250 mL round-bottom flask fitted with a magnetic stir bar wascharged with EX-6E (755 mg, 1.9 mmol) and trifluoroacetic acid (30 mL).This mixture was stirred at RT under an argon-flow atmosphere for 30 minand concentrated on a rotary evaporator. The residue was triturated withether (50 mL) and coevaporated with heptane (2×50 mL) to afford 801 mg(95% yield) of EX-6F as a clear yellow glass: ¹H NMR (300 MHz, DMSO-d₆)d 8.34-8.26 (m, 2H), 7.89 (d, J=7.8 Hz, 1H), 7.76 (t, J=7.9 Hz, 1H),7.20 (s, 1H), 4.51 (s, 2H), 3.57 (septet, J=6.6 Hz, 1H), 1.17 (d, J=6.6Hz, 6H); HRMS (ESI) calcd for C₁₅H₁₇N₄O₅ [M+H]⁺ of free base=333.1223,found 333.1199.

Prepared from EX-6F according to the procedure described for theCBZ-protected precursor to afford the product: ¹H NMR (300 MHz, CDCl₃) d9.34 (bs, 1H), 8.32 (s, 1H), 8.14 (d, J=8.0 Hz, 1H), 7.81 (t, J=7.8 Hz,2H), 7.53 (d, J=7.8 Hz, 2H), 7.47 (t, J=7.8 Hz, 1H), 7.39-7.25 (m, 5H),7.08 (s, 1H), 7.00 (d, J=7.8 Hz, 2H), 5.12 (s, 2H), 4.61 (d, J=7.8 Hz,1H), 4.35 (s, 2H), 4.21 (m, 1H), 3.50 (d of septets, 8 lines J=6.3 Hz,1H), 1.22 (d, J=6.3 Hz, 6H); ¹³C NMR (75 MHz, CDCl₃) d 168.5 (s), 167.4(s), 164.0 (s), 158.6 (s), 148.2 (s), 143.8 (s), 142.6 (s), 136.6 (s),136.2 (s), 135.0 (d), 133.4 (s), 133.2 (s), 129.9 (d), 128.7 (d), 128.3(d), 127.8 (d), 127.5 (d), 124.4 (d), 124.1 (d), 121.8 (d), 67.4 (t),49.9 (t), 44.1 (d), 43.2 (t), 22.4 (q); HRMS (ESI) calcd for C₃₁H₃₂N₇O₆[M+H]⁺: 598.2463, found 598.2414.

Prepared from EX-6G according to the method described for SC-81703 toafford the product: ¹H NMR (300 MHz, CD₃OD) d 9.25 (bs, 1H), 8.97 (m,1H), 8.78 (bs, 1H), 7.93-7.14 (complex m, 9H), 4.77 (s, 2H), 4.51 (s,3H), 3.66 (m, 1H), 1.30 (d, J=6.3 Hz, 6H); HRMS (ESI) calcd forC₂₃H₂₈N₇O₂ M+H]⁺=598 of free base 434.2304, found 434.2318.

Example 7

(EX-7A) Prepared from EX-6D using the same procedure described for EX-6Ewith the only exception that Cs₂CO₃ base was used. As such, EX-6D (213mg, 0.68 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester(166 mg, 1.02 mmol) and Cs₂CO₃ (771 mg, 2.37 mmol) afforded 143 mg ofEX-7A (61% yield) after flash chromatography (Merck 230-400 mesh SiO₂,2% MeOH in CHCl₃) as a slightly yellow glass: ¹H NMR (300 MHz, CDCl₃) d8.79-8.66 (m, 2H), 7.90-7.26 (complex m, 3H), 7.16 (s, 1H), 4.53 (s,2H), 3.57 (septet, J=6.3 Hz, 1H), 1.44 (s, 9H), 1.27 (d, J=6.3 Hz, 6H);HRMS (ESI) calcd for C₁₈H₂₅N₄O₃ [M+H]⁺=345.1927, found 345.1928.

(EX-7B) Prepared from EX-7A (143 mg, 0.41 mmol) using the same proceduredescribed for EX-6F to afford 212 mg (100% yield) of EX-7B as a yellowfoam: ¹H NMR (300 MHz, CDCl₃) d 8.72-8.64 (m, 2H), 7.95-7.89 (m, 1H),7.62-7.52 (complex m, 2H), 7.42-7.37 (m, 1H), 7.20 (s, 1H), 4.52 (s,2H), 3.57 (septet, J=6.3 Hz, 1H), 1.18 (d, J=6.3 Hz, 6H); HRMS (ESI)calcd for C₁₄H₁₇N₄O₃ [M+H]⁺ 289.1301, found 289.1296.

(EX-7C) Prepared from EX-7B using the same procedure described for theCBZ-protected materail to afford EX-7C; HRMS (ESI) calcd for C₃OH₃₂N₇O₄[M+H]⁺=554.2516, found 554.2523.

Prepared from EX-7C using the same procedure described for Example 6 toafford the product.

Example 8

By following the method of Example 6, the title compound was prepared:HRMS (ESI) calcd for C₂₄H₂₇N₇O₂ [M+H]⁺ 446.2304, found 446.2309.

Methylene analogs of pyrimidinones wherein a methylene is present as areplacement for the carbonyl of the acetamide at the N-3 position of thepyrimidinone can be prepared using Scheme 8 “A General MethylenePyrimidinone Preparation” as detailed below along with the specificExample 9.

Example 9

EX-9A) To a solution of[[5-[(benzyloxycarbonyl)amino]-2-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl]acetaldehydein tetrahydrofuran and dichloromethane (1:1, 0.3 M) is added a catalyticamount of acetic acid and 1 equivalent of the appropriate amine. Thesolution is cooled to 0° C. in an ice bath, and 1 equivalent sodiumtriacetoxyborohydride is added in one portion. After stirring for 5minutes, the ice bath is removed, and the reaction mixture is allowed tostir at room temperature for 2 hours. The reaction is quenched by theaddition of 1 N NaOH, and the mixture is stirred for 5 minutes. Typicalaqueous work up is followed by chromatographic purification to providepure product EX-9A.

EX-9B) To a solution of[5-[(benzyloxycarbonyl)amino]-2-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl]acetamide(EX-9A) in methanol (0.2 M) is added 10% Pd/C in one portion. Theresulting mixture is stirred under an atmosphere of hydrogen gas(balloon) at room temperature for approximately 16 hours. The crudereaction mixture is filtered through a pad of Celite 545, and thesolvent is removed under reduced pressure. Trituration of the residuefrom ethyl ether gives pure product EX-9B.

EX-9C) To a solution of[5-amino-2-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl]acetamide (EX-9B) intetrahydrofuran and dichloromethane (1:1, 0.3 M) is added a catalyticamount of acetic acid and 1 equivalent phenylacetaldehyde. The solutionis cooled to 0° C. in an ice bath, and 1 equivalent sodiumtriacetoxyborohydride is added in one portion. After stirring for 5minutes, the ice bath is removed, and the reaction mixture is allowed tostir at room temperature for 2 hours. The reaction is quenched by theaddition of 1 N NaOH, and the mixture is stirred for 5 minutes. Typicalaqueous work up is followed by chromatographic purification to providepure product EX-9C.

A solution of[5-(2-phenylethyl)amino-2-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl]acetamidein 4M HCl dioxane (0.2 M) is stirred for several hours. After thereaction is complete, the volatiles are removed under reduced pressure.The residue is purified by trituration with ethyl ether to afford pureproduct 5.

Sulfonyl analogs of pyrimidinones wherein a sulfonyl is present as areplacement for the carbonyl of the acetamide at the N-3 position of thepyrimidinone can be prepared using procedures generally based on thosedisclosed in Schemes 1-5 by substituting an appropriateaminomethanesulfonamide of an N-Boc-amidino-protected amine in place ofthe 1,1-dimethoxyethylamine. For example, theN-(4-amidinobenzyl)2-aminomethanesulfonamide can be used. Using thisapproach, sulfonyl analogs in Examples 10 and 11 can be prepared.

Example 10

Example 11

Triazinone analogs of pyrimidinones wherein a nitrogen is present as areplacement for the carbon at the 4-position of the pyrimidinone can beprepared using Scheme 9 “A General 4-Aza Pyrimidinone Preparation” asdetailed below along with the specific Example 12.

Example 12

EX-12) A solution of glycine t-butyl ester hydrochloride (1 mmol) indichloromethane is treated with benzoyl chloride (1 mmol) and triethylamine (2 mmol). The reaction mixture is allowed to stir at roomtemperature for 16 h. The mixture is washed with water and extractedwith dichloromethane. The combined organic layers are dried over MgSO₄.After removing the volatiles in vacuo pure product EX-12A is isolated.

EX-12B) A mixture of N-benzoylglycine t-butyl ester (1 mmol; EX-12A),Lawesson's reagent (0.5 mmol) and toluene are heated to 80° C. for 16 h.The reaction mixture is concentrated under reduced pressure.Purification via column chromatography on silica gel gives pure productEX-12B.

EX-12C) A mixture of N-thiobenzoylglycine t-butyl ester (1 mmol; EX-12B)in dichloromethane is treated with trimethyloxonium tetrafluoroborate(1.1 mmol) at −78° C. After stirring the reaction mixture for 2 h, themixture is washed with NaHCO₃ (aq) and extracted with dichloromethane.The combined organic layers are dried over MgSO₄ and filtered. Afterconcentration of the volatile organic components, the desired productEX-12C is isolated.

EX-12D) A solution of N-thiomethylbenzylglycine t-butyl ester (1 mmol;EX-12C) in methanol is treated with hydrazine (1 mmol). The volatilematerials are removed in vacuo, and the desired compound EX-12D isisolated without further purification.

EX-12E) A mixture of compound EX-12D (1 mmol) and ethyl thiooxamate (1mmol) in methanol is heated to reflux temperature for 4 h. Aprecipitation of colorless crystals occurs, and the crystals of thedesired product EX-12E are isolated by suction filtration.

A solution of compound EX-12E (1 mmol) and pyridine (5 mmol) inacetonitrile is treated with a solution of a-toluenesulfonyl chloride (3mmol) in acetonitrile. The reaction mixture is stirred at −10° C. to 0°C. for 3 h. A white precipitate forms after the reaction is complete.The crystals of the desired product EX-12F are isolated by suctionfiltration.

EX-12G) Trifluoroacetic acid is added to a mixture of compound EX-12F (1mmol)in anisole at 0° C. The reaction mixture is allowed to stir at 0°C. for 1 h. The reaction mixture is extracted with an organic solvent.Removal of the organic solvent under reduced pressure gives pure productEX-12G.

EX-12H) Compound EX-12G (1 mmol), EDC(1.3 mmol), and HOBt (1.3 mmol) aremixed in DMF, and the mixture is stirred at 20° C. for 15 minutes. Tothis mixture is added a solution ofbenzyl-[[(4-aminomethylphenyl)iminomethyl]amino]carbamate hydrogenchloride salt (1.3 mmol) and DIEA (1.3 mmol) in DMF. Typical aqueouswork-up is followed by chromatographic purification to provide thedesired product EX-12H.

Compound EX-12H (1 mmol), p-toluene sulfonic acid mono hydrate (1 mmol)and 10% Pd on activated carbon (0.1 mmol) are mixed with methanol. Themixture is stirred for 2 h under hydrogen atmosphere which is introducedand maintained through a rubber balloon. After filtering off thecatalyst and removing the methanol, the desired product is isolated.

Formula (I) compounds of this invention possessing hydroxyl, thiol, andamine functional groups can be converted to a wide variety derivatives.Alternatively, derivatized Formula (I) compounds can be obtained byfirst derivatizing one or more intermediates in the processes ofpreparation before further transforming the derivatized intermediate tocomounds of Formula (I). A hydroxyl group in the form of an alcohol orphenol can be readily converted to esters of carboxylic, sulfonic,carbamic, phosphonic, and phosphoric acids. Acylation to form acarboxylic acid ester is readily effected using a suitable acylatingreagent such as an aliphatic acid anhydride or acid chloride. Thecorresponding aryl and heteroaryl acid anhydrides and acid chlorides canalso be used. Such reactions are generally carried out using an aminecatalyst such as pyridine in an inert solvent. Similarly, carbamic acidesters (urethanes) can be obtained by reacting a hydroxyl group withisocyanates and carbamoyl chlorides. Sulfonate, phosphonate, andphosphate esters can be prepared using the corresponding acid chlorideand similar reagents. Compounds of Formula (I) that have at least onethiol group present can be converted to the corresponding thioestersderivatives analogous to those of alcohols and phenols using the samereagents and comparable reaction conditions. Compounds of Formula (I)that have at least one primary or secondary amine group present can beconverted to the corresponding amide derivatives. Amides of carboxylicacids can be prepared using the appropriate acid chloride or anhydrideswith reaction conditions analogous to those used with alcohols andphenols. Ureas of the corresponding primary or secondary amine can beprepared using isocyanates directly and carbamoyl chlorides in thepresence of an acid scavenger such as triethylamine or pyridine.Sulfonamides can be prepared from the corresponding sulfonyl chloride inthe presence of aqueous sodium hydroxide or a tertiary amine. Suitableprocedures and methods for preparing these derivatives can be found inHouse's Modern Synthetic Reactions, W. A. Benjamin, Inc., Shriner,Fuson, and Curtin in The Systematic Identification of Organic Compounds,5th Edition, John Wiley & Sons, and Fieser and Fieser in Reagents forOrganic Synthesis, Volume 1, John Wiley & Sons. Reagents of a widevariety that can be used to derivatize hydroxyl, thiol, and amines ofcompounds of Formula (I) are available from commercial sources or thereferences cited above, which are incorporated herein by reference.

Formula (I) compounds of this invention possessing hydroxyl, thiol, andamine functional groups can be alkylated to a wide variety ofderivatives. Alternatively, alkylated Formula (I) compounds can beobtained by first alkylating one or more intermediates in the processesof preparation before further transforming the alkylated intermediate tocomounds of Formula (I). A hydroxyl group of compounds of Formula (I)can be readily converted to ethers. Alkylation to form an ether isreadily effected using a suitable alkylating reagent such as an alkylbromide, alkyl iodide or alkyl sulfonate. The corresponding aralkyl,heteroaralkyl, alkoxyalkyl, aralkyloxyalkyl, and heteroaralkyloxyalkylbromides, iodides, and sulfonates can also be used. Such reactions aregenerally carried out using an alkoxide forming reagent such as sodiumhydride, potassium t-butoxide, sodium amide, lithium amide, and n-butyllithium using an inert polar solvent such as DMF, DMSO, THF, andsimilar, comparable solvents. amine catalyst such as pyridine in aninert solvent. Compounds of Formula (I) that have at least one thiolgroup present can be converted to the corresponding thioetherderivatives analogous to those of alcohols and phenols using the samereagents and comparable reaction conditions. Compounds of Formula (I)that have at least one primary, secondary or tertiary amine grouppresent can be converted to the corresponding secondary, tertiary orquaternary ammonium derivative. Quatemary ammonium derivatives can beprepared using the appropriate bromides, iodides, and sulfonatesanalogous to those used with alcohols and phenols. Conditions involvereaction of the amine by warming it with the alkylating reagent with astoichiometric amount of the amine (i.e., one equivalent with a tertiaryamine, two with a secondary, and three with a primary). With primary andsecondary amines, two and one equivalents, respectively, of an acidscavenger are used concurrently. Secondary or tertiary amines can beprepared from the corresponding primary or secondary amine. A primaryamine can be dialkylated by reductive amination using an aldehyde, suchas formaldehyde, and sodium cyanoborohydride in the presence of glacialacetic acid. A primary amine can be monoalkylated by firstmono-protecting the amine with a ready cleaved protecting group, such astrifluoroacetyl. An alkylating agent, such as dimethylsulfate, in thepresence of a non-nucleophilic base, such as Barton's base(2-tert-butyl-1,1,3,3-tetramethylguanidine), gives the monomethylatedprotected amine. Removal of the protecting group using aqueous potassiumhydroxide gives the desired monoalkylated amine. Additional suitableprocedures and methods for preparing these derivatives can be found inHouse's Modern Synthetic Reactions, W. A. Benjamin, Inc., Shriner,Fuson, and Curtin in The Systematic Identification of Organic Compounds,5th Edition, John Wiley & Sons, and Fieser and Fieser in Reagents forOrganic Synthesis published by John Wiley & Sons. Perfluoroalkylderivatives can be prepared as described by DesMarteau in J. Chem. Soc.Chem. Commun. 2241 (1998). Reagents of a wide variety that can be usedto derivatize hydroxyl, thiol, and amines of compounds of Formula (I)are available from commercial sources or the references cited above,which are incorporated herein by reference.

The results of the aforementioned synthetic approaches to thepreparation pyrimidinones by derivatization of a nucleophilicsubstituent such as may be present in B, R¹, R² and Y⁰ are shown inTable 1 for the specific Examples 13 through 19. The specific examplesrecited below should be considered a being merely illustrative of thewide variety possible and not as limiting to one of ordinary skill inthe art.

TABLE 1 Structures of Pyrimidinones Prepared by General DerivatizationProcedures

General Structure Ex. MW No. R² B—A— Y⁰ (m/z + 1) 13 phenylmethoxyacetyl 4-amidinobenzyl 449.47 14 phenyl 4-methylbenzoyl4-amidinobenzyl 495.54 15 phenyl 4-nitrobenzoyl 4-amidinobenzyl 526.5216 phenyl isobutyryl 4-amidinobenzyl 447.50 17 phenyl2,4,6-trimethylbenzoyl 4-amidinobenzyl 523.60 18 phenyl benzoyl4-amidinobenzyl 481.52 19 phenyl acetyl 4-amidobenzyl 419.45

Assays for Biological Activity TF-VIIa Assay

In this assay 100 nM recombinant soluble tissue factor and 2 nMrecombinant human factor VIIa are added to a 96-well assay platecontaining 0.4 mM of the substrate,N-Methylsulfonyl-D-phe-gly-arg-p-nitroaniline and either inhibitor orbuffer (5 mM CaCl₂, 50 mM Tris-HCl, pH 8.0, 100 mM NaCl, 0.1% BSA). Thereaction, in a final volume of 100 ul is measured immediately at 405 nmto determine background absorbance. The plate is incubated at roomtemperature for 60 min, at which time the rate of hydrolysis of thesubstrate is measured by monitoring the reaction at 405 nm for therelease of pnitroaniline. Percent inhibition of TF-VIIa activity iscalculated from OD_(405 nm) value from the experimental and controlsample.

Xa Assay

0.3 nM human factor Xa and 0.15 mMN-α-Benzyloxycarbonyl-D-arginyl-L-glycyl-L-arginine-p-nitroaniline-dihydrochloride(S-2765) are added to a 96-well assay plate containing either inhibitoror buffer (50 mM Tris-HCl, pH 8.0, 100 mM NaCl, 0.1% BSA). The reaction,in a final volume of 100 ul is measured immediately at 405 nm todetermine background absorbance. The plate is incubated at roomtemperature for 60 min, at which time the rate of hydrolysis of thesubstrate is measured by monitoring the reaction at 405 nm for therelease of p-nitroaniline. Percent inhibition of Xa activity iscalculated from OD_(405 nm) value from the experimental and controlsample.

Thrombin Assay

0.28 nM human thrombin and 0.06 mMH-D-Phenylalanyl-L-pipecolyl-L-arginine-pnitroaniline dihydrochlorideare added to a 96-well assay plate containing either inhibitor or buffer(50 mM Tris-HCl, pH 8.0, 100 mM NaCl, 0.1% BSA). The reaction, in afinal volume of 100 ul is measured immediately at 405 nm to determinebackground absorbance. The plate is incubated at room temperature for 60min, at which time the rate of hydrolysis of the substrate is measuredby monitoring the reaction at 405 nm for the release of mnitroaniline.Percent inhibition of thrfmbin activity is calculated from OD_(405 nm)value from the experimental and control sample.

Trypsin Assay

5 ug/ml trypsin, type IX from porcine pancreas and 0.375 mMN-α-Benzoyl-L-arginine-p-nitroanilide (L-BAPNA) are added to a 96-wellassay plate containing either inhibitor or buffer (50 mM Tris-HCl, pH8.0, 100 mM NaCl, 0.1% BSA). The reactions, in a final volume of 100 ulare measured immediately at 405 nm to determine background absorbance.The plate is incubated at room temperature for 60 min, at which time therate of hydrolysis of the substrate is measured by monitoring thereaction at 405 nm for the release of p-nitroaniline. Percent inhibitionof trypsin activity is calculated from OD_(405 nm) value from theexperimental and control sample.

Recombinant soluble TF, consisting of amino acids 1-219 of the matureprotein sequence was expressed in E. coli and purified using a Mono QSepharose FPLC. Recombinant human VIIa was purchased from AmericanDiagnostica, Greenwich Conn. and chromogenic substrateN-Methylsulfonyl-D-phe-gly-arg-p-nitroaniline was prepared by AmericanPeptide Company, Inc., Sunnyvale, Calif. Factor Xa was obtained fromEnzyme Research Laboratories, South Bend Ind., thrombin from Calbiochem,La Jolla, Calif., and trypsin and L-BAPNA from Sigma, St. Louis Mo. Thechromogenic substrates S-2765 and were purchased from Chromogenix,Sweden.

The biological activity of the compounds of Examples 1 through 19 asdetermined by the bioassay procedures is summarized in the Table 2.

TABLE 2 Inhibitory Activity of Pyrimidinones toward Factor Xa, TF-VIIA,Thrombin II, and Trypsin II. Example TF-VIIA Thrombin II Factor XaTrpysin II Number IC50 (uM) IC50 (uM) IC50 (uM) IC50 (uM) 1 15.4 22.4 —0.5 2 >30 >30 — >30 3 1.0 1.0 — 0.6 4 — — — — 5 — — — — 6 0.05 43% @ 30uM 33% @ 30 uM <0.04 7 0.7 11.3 33% @ 30 uM 0.04 8 0.08 42% @ 30 uM 15%@ 30 uM 0.04 9 — — — — 10 — — — — 11 — — — — 12 — — — — 13 — — — — 14 —— — — 15 — — — — 16 — — — — 17 — — — — 18 — — — — 19 — — — —

What we claim is:
 1. A compound having the Formula:

or a pharmaceutically acceptable salt thereof, wherein; B is:

R³², R³³, R³⁴, R³⁵, and R³⁶ are independently selected from the groupconsisting of hydrogen, acetamido, haloacetamido, amidino, guanidino,alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio,amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl,halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy,carboxamido, cyano, and Q^(b); A is selected from the group consistingof single covalent bond and (CH(R¹⁵))_(pa)—(W⁷)_(rr) wherein rr is aninteger selected from 0 through 1, pa is an integer selected from 0through 3, and W⁷ is N(R⁷); R⁷ is selected from the group consisting ofhydrogen and alkyl; R¹⁵ is selected from the group consisting ofhydrogen, halo, alkyl, and haloalkyl; M is R¹—C; R¹ is selected from thegroup consisting of hydrogen, hydroxy, hydroxyamino, amidino, amino,cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio,alkoxyamino, haloalkyl, haloalkoxy, and halo; R² is Z⁰—Q; Z” is acovalent single bond; Q is selected from the group consisting of aryland 5- or 6-membered heteroaryl wherein the heteroatoms of saidheteroaryl are selected from oxygen, nitrogen, and sulfur and (a) a ringcarbon in a first alpha position relative to the ring carbon at thepoint of attachment is optionally substituted by R⁹, (b) a ring carbonin a second alpha position relative to the ring carbon at the point ofattachment is optionally substituted by R¹³, (c) a ring carbon, in afirst beta position relative to the ring carbon at the point ofattachment and in an alpha position relative to the ring atom optionallysubstituted by R⁹, is optionally substituted by R¹⁰, (d) a ring carbon,in a second beta position relative to the ring carbon at the point ofattachment and in an alpha position relative to the ring atom optionallysubstituted by R¹³, is optionally substituted by R¹², and (e) a ringcarbon, if present, in the gamma position relative to the ring carbon atthe point of attachment and in an alpha position relative to each of thering atoms optionally substituted by R¹⁰ and R¹², respectively, isoptionally substituted by R¹¹; R⁹, R¹¹, and R¹³ are independentlyselected from the group consisting of hydrogen, hydroxy, amino, amidino,guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulfinyl,alkylsulfonyl, amidosulfonyl, monoalkylamidosulfonyl, alkyl, halo,haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano;R¹⁰ and R¹² are independently selected from the group consisting ofhydrogen, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy,alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino,alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkylamidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl, carboalkoxy,carboxy, carboxyamido, carboxyalkyl, and cyano; Y⁰ is formula (IV):

 wherein D⁵, D⁶, J⁵, and J⁶ are independently selected from the groupconsisting of C, N, O, S and a covalent bond with the provisos that nomore than one is a covalent bond, no more than one of D⁵, D⁶, J⁵, and J⁶is O, no more than one of D⁵, D⁶, J⁵, and J⁶ is S, one of D⁵, D⁶, J⁵,and J⁶ must be a covalent bond when two of D⁵, D⁶, J⁵, and J⁶ are O andS, and no more than four of D⁵, D⁶, J⁵, and J⁶ are N; R¹⁶, R¹⁷, R¹⁸, andR¹⁹ are independently selected from the group consisting of hydrogen,amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino,lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl,haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl,aminoalkyl, and cyano; Q^(b) is selected from the group consisting ofhydrogen, NR²⁰R²¹, and C(NR²⁵)NR²³R²⁴; R²⁰, R²¹, R²³, R²⁴, and R²⁵ areindependently selected from the group consisting of hydrogen and alkyl;and Q^(s) is CH₂.
 2. The compound as recited in claim 1 or apharmaceutically acceptable salt thereof, wherein;

R³², R³³, R³⁴, R³⁵, and R³⁶ are independently selected from the groupconsisting of hydrogen, amidino, guanidino, methyl, ethyl, methoxy,ethoxy, hydroxy, amino, N-methylamino, dimethylamino, methylthio,ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl,fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl,hydroxymethyl, amidocarbonyl, carboxy, cyano, and Q^(b); A is selectedfrom the group consisting of single covalent bond, NH, N(CH₃), CH₂,CH₃CH, and CH₂CH₂; M is R¹—C; R¹ is selected from the group consistingof hydrogen, hydroxy, amino, amidino, hydroxyamino, aminomethyl,methylamino, cyano, methyl, trifluoromethyl, methoxy, hydroxymethyl,methoxyamino, methylthio, trifluoromethoxy, fluoro, and chloro; R² isselected from the group consisting of phenyl, and 2-thienyl, 2-furyl,2-pyrrolyl, 2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl, and3-pyridyl heteroaryl rings, wherein (a) a ring carbon in a first alphaposition relative to the ring carbon at the point of attachment isoptionally substituted by R⁹, (b) a ring carbon in a second alphaposition relative to the ring carbon at the point of attachment isoptionally substituted by R¹³, (c) a ring carbon, in a first betaposition relative to the ring carbon at the point of attachment and inan alpha position relative to the ring atom optionally substituted byR⁹, is optionally substituted by R¹⁰, (d) a ring carbon, in a secondbeta position relative to the ring carbon at the point of attachment andin an alpha position relative to the ring atom optionally substituted byR¹³, is optionally substituted by R¹², and (e) a ring carbon, ifpresent, in the gamma position relative to the ring carbon at the pointof attachment and in an alpha position relative to each of the ringatoms optionally substituted by R¹⁰ and R¹², respectively, is optionallysubstituted by R¹¹; R⁹, R¹¹, and R¹³ are independently selected from thegroup consisting of hydrogen, methyl, ethyl, methoxy, ethoxy, hydroxy,amino, N-methylamino, N,N-dimethylamino, methylthio, trifluoromethyl,pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo,amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl,hydroxymethyl, 1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl,carboxy, and cyano; R¹⁰ and R¹² are independently selected from thegroup consisting of hydrogen, amidino, amidocarbonyl,N-methylamidocarbonyl, guanidino, methyl, ethyl, methoxy, ethoxy,hydroxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, carboxy,carboxymethyl, amino, acetamido, trifluoromethyl, pentafluoroethyl,2,2,2-trifluoroethyl, trifluoroacetamido, aminomethyl, N-methylamino,dimethylamino, amidosulfonyl, N-methylamidosulfonyl,N,N-dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo, andcyano; Y⁰ is selected from the group consisting of:

R¹⁶, R¹⁷, R¹⁸, and R¹⁹ are independently selected from the groupconsisting of hydrogen, methyl, ethyl, amidino, guanidino, methoxy,hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino,dimethylamino, methylthio, ethylthio, trifluoromethylthio,methylsulfinyl, methylsulfonyl, trifluoromethyl, pentafluoroethyl,2,2,2-trifluoroethyl, trifluoromethoxy, fluoro, chloro, amidosulfonyl,N-methylamidosulfonyl, hydroxymethyl, carboxy, and cyano; Q^(b) isselected from the group consisting of NR²⁰R²¹ and C(NR²⁵)NR²³R²⁴; R²⁰,R²¹, R²³, R²⁴, and R²⁵ are independently selected from the groupconsisting of hydrogen, methyl, and ethyl; and Q^(s) is CH₂.
 3. Thecompound as recited in claim 2 or a pharmaceutically acceptable saltthereof, wherein; B is selected from the group consisting of2-aminophenyl, 3-aminophenyl, 3-amidinophenyl, 4-amidinophenyl,3-carboxyphenyl, 3-carboxy-5-hydroxyphenyl, 3-chlorophenyl,4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl,3,4-difluorophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl,3-methoxyaminophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-methylphenyl,4-methylphenyl, and phenyl; A is selected from the group consisting ofCH₂, CH₃CH, CF₃CH, NHC(O), CH₂CH₂, and CH₂CH₂CH₂; M is R¹—C; R¹ isselected from the group consisting of hydrogen, hydroxy, amino, methyl,trifluoromethyl, fluoro, and chloro; R² is selected from the groupconsisting of 5-amino-3-amidocarbonylphenyl, 5-amino-2-fluorophenyl,3-amino-5-hydroxymethylphenyl, 5-amino-3-methoxycarbonylphenyl,3-amidinophenyl, 3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl,3-aminophenyl, benzyl, 3-carboxyphenyl, 3-carboxy-5-aminophenyl,3-carboxy-5-hydroxyphenyl, 3-carboxymethyl-5-aminophenyl,3-carboxymethyl-5-hydroxyphenyl, 3-carboxymethylphenyl, 3-chlorophenyl,2-chlorophenyl, 3-cyanophenyl, 3-dimethylaminophenyl, 2-fluorophenyl,3-fluorophenyl, 2,5-difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl,3-methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl,3-methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl,3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl,phenyl, 3-trifluoroacetamidophenyl, 3-trifluoromethylphenyl,2-trifluoromethylphenyl, 5-amino-2-thienyl, 5-amino-3-thienyl,3-bromo-2-thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl, and 3-thienyl; Y⁰ isselected from the group consisting of:

R¹⁶ and R¹⁹ are independently selected from the group consisting ofhydrogen, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy,hydroxymethyl, fluoro, chloro, and cyano; R¹⁷ and R¹⁸ are independentlyselected from the group consisting of hydrogen, fluoro, chloro, hydroxy,hydroxymethyl, amino, carboxy, and cyano; Q^(b) is selected from thegroup consisting of hydrogen and C(NR²⁵)NR²³R²⁴; R²³, R²⁴, and R²⁵ areindependently selected from the group consisting of hydrogen and methyl;and Q^(s) is CH₂.
 4. The compound as recited in claim 3 or apharmaceutically acceptable salt thereof, wherein; B is selected fromthe group consisting of 3-aminophenyl, 3-amidinophenyl, 4-amidinophenyl,3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl,4-methylphenyl, and phenyl; A is selected from the group consisting ofCH₂, NHC(O), CH₂CH₂, and CH₂CH₂CH₂; M is R¹—C; R¹ is selected from thegroup consisting of hydrogen, fluoro, and chloro; R² is selected fromthe group consisting of 3-aminophenyl, benzyl, 3-chlorophenyl,3-dimethylaminophenyl, 3-hydroxyphenyl, 3-methanesulfonylaminophenyl,3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl, phenyl,3-trifluoroacetamidophenyl, 3-bromo-2-thienyl, 2-thienyl, and 3-thienyl;and Y⁰ is selected from the group consisting of5-amidino-2-thienylmethyl, 4-amidinobenzyl, 2-fluoro-4-amidinobenzyl,and 3-fluoro-4-amdinobenzyl.
 5. A compound of claim 1, or apharmaceutically acceptable salt thereof,

 wherein: R² is 3-aminophenyl, B is 3-chlorophenyl, A is CH₂CH₂, Y⁰ is4-amidinobenzyl, and M is CH; R² is 3-aminophenyl, B is phenyl, A isCH₂, Y⁰ is 4-amidinobenzyl, and M is CH; R² is phenyl, B is3-chlorophenyl, A is CH₂CH₂, Y⁰ is 4-amidinobenzyl, and M is CH; R² is3-dimethylaminophenyl, B is phenyl, A is CH₂CH₂, Y⁰ is 4-amidinobenzyl,and M is CH; R² is 2-methylphenyl, B is phenyl, A is CH₂CH₂, Y⁰ is4-amidinobenzyl, and M is CH; R² is phenyl, B is 3-aminophenyl, A isC(O)NH, Y⁰ is 4-amidinobenzyl, and M is CH; R² is phenyl, B is3-amidinophenyl, A is CH₂, Y⁰ is 4-amidinobenzyl, and M is CH; R² is3-(N-methylamino)phenyl, B is phenyl, A is CH₂CH₂, Y⁰ is4-amidinobenzyl, and M is CH; R² is 3-methylsulfonamidophenyl, B isphenyl, A is CH₂CH₂, Y⁰ is 4-amidinobenzyl, and M is CH; R² is phenyl, Bis 4-amidinophenyl, A is CH₂, Y⁰ is 4-amidinobenzyl, and M is CH; R² is3-methylaminophenyl, B is phenyl, A is CH₂CH₂, Y⁰ is 4-amidinobenzyl,and M is CH; R² is phenyl, B is phenyl, A is CH₂, Y⁰ is 4-amidinobenzyl,and M is CH; R² is 3-methylphenyl, B is 4-phenyl, A is CH₂CH₂, Y⁰ is4-amidinobenzyl, and M is CH; R² is 3-aminophenyl, B is 3-chlorophenyl,A is CH₂CH₂, Y⁰ is 4-amidinobenzyl, and M is CCl; R² is 3-aminophenyl, Bis phenyl, A is CH₂, Y⁰ is 4-amidinobenzyl, and M is CCl; R² is phenyl,B is 3-chlorophenyl, A is CH₂CH₂, Y⁰ is 4-amidinobenzyl, and M is CCl;R² is 3-dimethylaminophenyl, B is phenyl, A is CH₂CH₂, Y⁰ is4-amidinobenzyl, and M is CCl; R² is 2-methylphenyl, B is phenyl, A isCH₂CH₂, Y⁰ is 4-amidinobenzyl, and M is CCl; R² is phenyl, B is3-aminophenyl, A is C(O)NH, Y⁰ is 4-amidinobenzyl, and M is CCl; R² isphenyl, B is 3-amidinophenyl, A is CH₂, Y⁰ is 4-amidinobenzyl, and M isCCl; R² is 3-(N-methylamino)phenyl, B is phenyl, A is CH₂CH₂, Y⁰ is4-amidinobenzyl, and M is CCl; R² is 3-methylsulfonamidophenyl, B isphenyl, A is CH₂CH₂, Y⁰ is 4-amidinobenzyl, and M is CCl; R² is phenyl,B is 4-amidinophenyl, A is CH₂, Y⁰ is 4-amidinobenzyl, and M is CCl; R²is 3-methylaminophenyl, B is phenyl, A is CH₂CH₂, Y⁰ is 4-amidinobenzyl,and M is CCl; R² is phenyl, B is phenyl, A is CH₂, Y⁰ is4-amidinobenzyl, and M is CCl; R² is 3-methylphenyl, B is 4-phenyl, A isCH₂CH₂, Y⁰ is 4-amidinobenzyl, and M is CCl; R² is 3-aminophenyl, B is3-chlorophenyl, A is CH₂CH₂, Y⁰ is 4-amidinobenzyl, and M is CF; R² is3-aminophenyl, B is phenyl, A is CH₂, Y⁰ is 4-amidinobenzyl, and M isCF; R² is phenyl, B is 3-chlorophenyl, A is CH₂CH₂, Y⁰ is4-amidinobenzyl, and M is CF; R² is 3-dimethylaminophenyl, B is phenyl,A is CH₂CH₂, Y⁰ is 4-amidinobenzyl, and M is CF; R² is 2-methylphenyl, Bis phenyl, A is CH₂CH₂, Y⁰ is 4-amidinobenzyl, and M is CF; R² isphenyl, B is 3-aminophenyl, A is C(O)NH, Y⁰ is 4-amidinobenzyl, and M isCF; R² is phenyl, B is 3-amidinophenyl, A is CH₂, Y⁰ is 4-amidinobenzyl,and M is CF; R² is 3-(N-methylamino)phenyl, B is phenyl, A is CH₂CH₂, Y⁰is 4-amidinobenzyl, and M is CF; R² is 3-methylsulfonamidophenyl, B isphenyl, A is CH₂CH₂, Y⁰ is 4-amidinobenzyl, and M is CF; R² is phenyl, Bis 4-amidinophenyl, A is CH₂, Y⁰ is 4-amidinobenzyl, and M is CF; R² is3-methylaminophenyl, B is phenyl, A is CH₂CH₂, Y⁰ is 4-amidinobenzyl,and M is CF; R² is phenyl, B is phenyl, A is CH₂, Y⁰ is 4-amidinobenzyl,and M is CF; or R² is 3-methylphenyl, B is 4-phenyl, A is CH₂CH₂, Y⁰ is4-amidinobenzyl, and M is CF.
 6. A compound having the Formula:

or a pharmaceutically acceptable salt thereof, wherein; B is selectedfrom the group consisting of hydrogen, C2—C8 alkyl, C3-C8 alkenyl, C3-C8alkynyl, and C2-C8 haloalkyl, wherein each member of group B isoptionally substituted at any carbon up to and including 6 atoms fromthe point of attachment of B to A with one or more of the groupconsisting of R³², R³³, R³⁴, R³⁵, and R³⁶; R³², R³³, R³⁴, R³⁵, and R³⁶are independently selected from the group consisting of hydrogen,acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino,alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkylamidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl,haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, andQ^(b); A is selected from the group consisting of single covalent bondand (CH(R¹⁵))_(pa)—(W⁷)_(rr) wherein rr is an integer selected from 0through 1, pa is an integer selected from 0 through 3, and W⁷ is N(R⁷);R⁷ is selected from the group consisting of hydrido and alkyl; R¹⁵ isselected from the group consisting of hydrtdo hydrogen, halo, alkyl, andhaloalkyl; M is R¹—C; R¹ is selected from the group consisting ofhydrogen, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl,alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino,haloalkyl, haloalkoxy, and halo; R² is Z⁰—Q; Z⁰ is a covalent singlebond; Q is selected from the group consisting of aryl and 5- or6-membered heteroaryl wherein the heteroatoms of said heteroaryl areselected from oxygen, nitrogen, and sulfur and (a) a ring carbon in afirst alpha position relative to the ring carbon at the point ofattachment is optionally substituted by R⁹, (b) a ring carbon in asecond alpha position relative to the ring carbon at the point ofattachment is optionally substituted by R¹³, (c) a ring carbon, in afirst beta position relative to the ring carbon at the point ofattachment and in an alpha position relative to the ring atom optionallysubstituted by R⁹, is optionally substituted by R¹⁰, (d) a ring carbon,in a second beta position relative to the ring carbon at the point ofattachment and in an alpha position relative to the ring atom optionallysubstituted by R¹³, is optionally substituted by R¹², and (e) a ringcarbon, if present, in the gamma position relative to the ring carbon atthe point of attachment and in an alpha position relative to each of thering atoms optionally substituted by R¹⁰ and R¹², respectively, isoptionally substituted by R¹¹; R⁹, R¹¹, and R¹³ are independentlyselected from the group consisting of hydrogen, hydroxy, amino, amidino,guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulfinyl,alkylsulfonyl, amidosulfonyl, monoalkylamidosulfonyl, alkyl, halo,haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano;R¹⁰ and R¹² are independently selected from the group consisting ofhydrogen, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy,alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino,alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkylamidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl, carboalkoxy,carboxy, carboxyamido, carboxyalkyl, and cyano; Y⁰ is formula (IV):

 wherein D⁵, D⁶, J⁵, and J⁶ are independently selected from the groupconsisting of C, N, O, S and a covalent bond with the provisos that nomore than one is a covalent bond, no more than one of D⁵, D⁶, J⁵, and J⁶is O, no more than one of D⁵, D⁶, J⁵, and J⁶ is S, one of D⁵, D⁶, J⁵,and J⁶ must be a covalent bond when two of D⁵, D⁶, J⁵, and J⁶ are O andS, and no more than four of D⁵, D⁶, J⁵, and J⁶ are N; R¹⁶, R¹⁷, R¹⁸, andR¹⁹ are independently selected from the group consisting of hydrogen,amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino,lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl,haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl,aminoalkyl, and cyano; Q^(b) is selected from the group consisting ofhydrogen, NR²⁰R²¹, N(R²⁶)C(NR²⁵)N(R²³)(R²⁴), and C(NR²⁵)NR²³R²⁴; R²⁰,R²¹, R²³, R²⁴, R²⁵, and R²⁶ are independently selected from the groupconsisting of hydrogen and alkyl; and Q^(s) is CH₂.
 7. The compound asrecited in claim 6 or a pharmaceutically acceptable salt thereof,wherein; B is selected from the group consisting of hydrogen, ethyl,2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butenyl, 2-butynyl,sec-butyl, tert-butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl,3-pentenyl, 2-pentynyl, 3-pentynyl, 2-pentyl, 3-pentyl, 2-methylbutyl,2-methyl-2-butenyl, 3-methylbutyl, 3-methyl-2-butenyl, 1-hexyl,2-hexenyl, 3-hexenyl, 4-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl,2-hexyl, 1-methyl-2-pentenyl, 1-methyl-3-pentenyl, 1-methyl-2-pentynyl,1-methyl-3-pentynyl, 3-hexyl, 1-ethyl-2-butenyl, 1-heptyl, 2-heptenyl,3-heptenyl, 4-heptenyl, 5-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl,5-heptynyl, 2-heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl,1-methyl-4-hexenyl, 1-methyl-2-hexynyl, 1-methyl-3-hexynyl,1-methyl-4-hexynyl, 3-heptyl, 1-ethyl-2-pentenyl, 1-ethyl-3-pentenyl,1-ethyl-2-pentynyl, 1-ethyl-3-pentynyl, 2,2,2-trifluoroethyl,2,2-difluoropropyl, 4-trifluoromethyl-5,5,5-trifluoropentyl,4-trifluoromethylpentyl, 5,5,6,6,6-pentafluorohexyl, and3,3,3-trifluoropropyl, wherein each member of group B is optionallysubstituted at any carbon up to and including 5 atoms from the point ofattachment of B to A with one or more of the group consisting of R³²,R³³, R³⁴, R³⁵ and R³⁶; R³², R³³, R³⁴, R³⁵, and R³⁶ are independentlyselected from the group consisting of hydrogen, amidino, guanidino,methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino,dimethylamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl,2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl,N-methylamidosulfonyl, hydroxymethyl, amidocarbonyl, carboxy, cyano, andQ^(b); A is selected from the group consisting of: (i) single covalentbond, NH, N(CH₃), CH₂, CH₃CH, and CH₂CH₂; and (ii) CH₂N(CH₃),CH₂N(CH₂CH₃), CH₂CH₂N(CH₃), and CH₂CH₂N(CH₂CH₃), with the proviso that Bis hydrogen; M is R¹—C; R¹ is selected from the group consisting ofhydrogen, hydroxy, amino, amidino, hydroxyamino, aminomethyl,methylamino, cyano, methyl, trifluoromethyl, methoxy, hydroxymethyl,methoxyamino, methylthio, trifluoromethoxy, fluoro, and chloro; R² isselected from the group consisting of phenyl, and 2-thienyl, 2-furyl,2-pyrrolyl, 2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl, and3-pyridyl heteroaryl rings, wherein (a) a ring carbon in a first alphaposition relative to the ring carbon at the point of attachment isoptionally substituted by R⁹, (b) a ring carbon in a second alphaposition relative to the ring carbon at the point of attachment isoptionally substituted by R¹³, (c) a ring carbon, in a first betaposition relative to the ring carbon at the point of attachment and inan alpha position relative to the ring atom optionally substituted byR⁹, is optionally substituted by R¹⁰, (d) a ring carbon, in a secondbeta position relative to the ring carbon at the point of attachment andin an alpha position relative to the ring atom optionally substituted byR¹³, is optionally substituted bv R¹², and (e) a ring carbon, ifpresent, in the gamma position relative to the ring carbon at the pointof attachment and in an alpha position relative to each of the ringatoms optionally substituted by R¹⁰ and R¹², respectively, is optionallysubstituted by R¹¹; R⁹, R¹¹, and R¹³ are independently selected from thegroup consisting of hydrogen, methyl, ethyl, methoxy, ethoxy, hydroxy,amino, N-methylamino, N,N-dimethylamino, methylthio, trifluoromethyl,pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo,amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl,hydroxymethyl, 1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl,carboxy, and cyano; R¹⁰ and R¹² are independently selected from thegroup consisting of hydrogen, amidino, amidocarbonyl,N-methylamidocarbonyl, guanidino, methyl, ethyl, methoxy, ethoxy,hydroxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, carboxy,carboxymethyl, amino, acetamido, trifluoromethyl, pentafluoroethyl,2,2,2-trifluoroethyl, trifluoroacetamido, aminomethyl, N-methylamino,dimethylamino, amidosulfonyl, N-methylamidosulfonyl,N,N-dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo, andcyano; Y⁰ is selected from the group consisting of:

R¹⁶, R¹⁷, R¹⁸, and R¹⁹ are independently selected from the groupconsisting of hydrogen, methyl, ethyl, amidino, guanidino, methoxy,hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino,dimethylamino, methylthio, ethylthio, trifluoromethylthio,methylsulfinyl, methylsulfonyl, trifluoromethyl, pentafluoroethyl,2,2,2-trifluoroethyl, trifluoromethoxy, fluoro, chloro, amidosulfonyl,N-methylamidosulfonyl, hydroxymethyl, carboxy, and cyano; Q^(b) isselected from the group consisting of NR²⁰R²¹, C(NR²⁵)NR²³R²⁴, andN(R²⁶)C(NR²⁵)N(R²³)(R²⁴); R²⁰, R²¹, R²³, R²⁴, R²⁵, and R²⁶ areindependently selected from the group consisting of hydrogen, methyl,and ethyl; and Q^(s) is CH₂.
 8. The compound as recited in claim 7 or apharmaceutically acceptable salt thereof, wherein; B is selected fromthe group consisting of hydrogen, ethyl, 2-propenyl, 2-propynyl, propyl,isopropyl, butyl, 2-butyl, (R)-2-butyl,(S)-2-butyl, tert-butyl,isobutyl, 1-pentyl, 3-pentyl, 2-methylbutyl, 2,2,2-trifluoroethyl,6-amidocarbonylhexyl, 4-methyl-2-pentyl, 3-hydroxypropyl,3-methoxy-2-propyl, 2-methoxyethyl, 2-methyl-2-butyl, 3-methyl-2-butyl,2-dimethylaminopropyl, 2-cyanoethyl, 6-hydroxyhexyl, 2-hydroxyethyl,2-amidinoethyl, 2-guanidinoethyl, 3-guanidinopropyl, 4-guanidinobutyl,3-hydroxypropyl, 4-hydroxybutyl, 6-cyanohexyl, 2-dimethylaminoethyl,3-methylbutyl, 2-methylbutyl, (S)-2-methylbutyl, 3-aminopropyl, 2-hexyl,and 4-aminobutyl; A is selected from the group consisting of singlecovalent bond, CH₂, CH₃CH, and CH₂CH₂; M is R¹—C; R¹ is selected fromthe group consisting of hydrogen, hydroxy, amino, methyl,trifluoromethyl, fluoro, and chloro; R² is selected from the groupconsisting of 5-amino-3-amidocarbonylphenyl, 5-amino-2-fluorophenyl,3-amino-5-hydroxymethylphenyl, 5-amino-3-methoxycarbonylphenyl,3-amidinophenyl, 3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl,3-aminophenyl, benzyl, 3-carboxyphenyl, 3-carboxy-5-aminophenyl,3-carboxy-5-hydroxyphenyl, 3-carboxymethyl-5-aminophenyl,3-carboxymethyl-5-hydroxyphenyl, 3-carboxymethylphenyl, 3-chlorophenyl,2-chlorophenyl, 2,6-dichlorophenyl, 3-cyanophenyl,3-dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl,2,5-difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl,3-methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl,3-methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl,3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl,phenyl, 3-trifluoroacetamidophenyl, 3-trifluoromethylphenyl,2-trifluoromethylphenyl, 5-amino-2-thienyl, 5-amino-3-thienyl,3-bromo-2-thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl, and 3-thienyl; Y⁰ isselected from the group consisting of:

R¹⁶ and R¹⁹ are independently selected from the group consisting ofhydrogen, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy,hydroxymethyl, fluoro, chloro, and cyano; R¹⁷ and R¹⁸ are independentlyselected from the group consisting of hydrogen, fluoro, chloro, hydroxy,hydroxymethyl, amino, carboxy, and cyano; Q^(b) is selected from thegroup consisting of hydrogen and C(NR²⁵)NR²³R²⁴; R²³, R²⁴, and R²⁵ areindependently selected from the group consisting of hydrogen and methyl;and Q^(s) is CH₂.
 9. The compound as recited in claim 8 or apharmaceutically acceptable salt thereof, wherein; B is selected fromthe group consisting of hydrogen, ethyl, 2-propenyl, 2-propynyl, propyl,isopropyl, butyl, 2-butyl, (R)-2-butyl,(S)-2-butyl, tert-butyl,isobutyl, 1-pentyl, 3-pentyl, 2-methylbutyl, 2,2,2-trifluoroethyl,6-amidocarbonylhexyl, 4-methyl-2-pentyl, 3-hydroxypropyl,3-methoxy-2-propyl, 2-methoxyethyl, 2-methyl-2-butyl, 3-methyl-2-butyl,2-dimethylaminopropyl, 2-cyanoethyl, 6-hydroxyhexyl, 2-hydroxyethyl,2-amidinoethyl, 2-guanidinoethyl, 3-guanidinopropyl, 4-guanidinobutyl,3-hydroxypropyl, 4-hydroxybutyl, 6-cyanohexyl, 2-dimethylaminoethyl,3-methylbutyl, 2-methylbutyl, (S)-2-methylbutyl, 3-aminopropyl, 2-hexyl,and 4-aminobutyl; A is selected from the group consisting of singlecovalent bond, CH₂, CH₃CH, and CH₂CH₂; M is R¹—C; R¹ is selected fromthe group consisting of hydrogen, fluoro, and chloro; R² is selectedfrom the group consisting of 5-amino-2-fluorophenyl,3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl, 3-aminophenyl,3-carboxyphenyl, 3-cyanophenyl, 3-methoxycarbonylphenyl, phenyl, and3-pyridyl; and Y⁰ is selected from the group consisting of5-amidino-2-thienylmethyl, 4-amidinobenzyl, 2-fluoro-4-amidinobenzyl,and 3-fluoro-4-amidinobenzyl.
 10. A compound of claim 6, or apharmaceutically acceptable salt thereof,

wherein: R² is 3-aminophenyl, B is 2,2,2-trifluoroethyl, A is singlebond, Y⁰ is 4-amidinobenzyl, and M is CH; R² is 3-aminophenyl, B is(S)-2-butyl, A is single bond, Y⁰ is 4-amidinobenzyl, and M is CH; R² is5-amino-2-fluorophenyl, B is isopropyl, A is single bond, Y⁰ is4-amidinobenzyl, and M is CH; R² is 2-methyl-3-aminophenyl, B isisopropyl, A is single bond, Y⁰ is 4-amidinobenzyl, and M is CH; R² is3-aminophenyl, B is ethyl, A is single bond, Y⁰ is 4-amidinobenzyl, andM is CH; R² is 3-aminophenyl, B is ethyl, A is single bond, Y⁰ is4-amidino-2-fluorobenzyl, and M is CH; R² is 3-aminophenyl, B is2-propenyl, A is single bond, Y⁰ is 4-amidinobenzyl, and M is CH; R² is3-aminophenyl, B is isopropyl, A is single bond, Y⁰ is4-amidino-2-fluorobenzyl, and M is CH; R² is 3-aminophenyl, B isisopropyl, A is single bond, Y⁰ is 4-amidinobenzyl, and M is CH; R² is3-aminophenyl, B is 2-butyl, A is single bond, Y⁰ is 4-amidinobenzyl,and M is CH; R² is 3-aminophenyl, B is (R)-2-butyl, A is single bond, Y⁰is 4-amidinobenzyl, and M is CH; R² is 3-aminophenyl, B is 2-propynyl, Ais single bond, Y⁰ is 4-amidinobenzyl, and M is CH; R² is 3-aminophenyl,B is 3-pentyl, A is single bond, Y⁰ is 4-amidinobenzyl, and M is CH; R²is 3-aminophenyl, B is hydrogen, A is CH₂, Y⁰ is 4-amidinobenzyl, and Mis CH; R² is 3-aminophenyl, B is ethyl, A is CH₂, Y⁰ is 4-amidinobenzyl,and M is CH; R² is 3-aminophenyl, B is 2-methypropyl, A is single bond,Y⁰ is 4-amidinobenzyl, and M is CH; R² is 3-aminophenyl, B is 2-propyl,A is CH₃CH, Y⁰ is 4-amidinobenzyl, and M is CH; R² is 3-aminophenyl, Bis propyl, A is single bond, Y⁰ is 4-amidino-2-fluorobenzyl, and M isCH; R² is 3-aminophenyl, B is 6-amidocarbonylhexyl, A is single bond, Y⁰is 4-amidinobenzyl, and M is CH; R² is 3-aminophenyl, B is tert-butyl, Ais single bond, Y⁰ is 4-amidinobenzyl, and M is CH; R² is 3-aminophenyl,B is tert-butyl, A is single bond, Y⁰ is 4-amidinobenzyl, and M is CH;R² is 3-aminophenyl, B is 3-hydroxypropyl, A is single bond, Y⁰ is4-amidinobenzyl, and M is CH; R² is 3-aminophenyl, B is 2-methylpropyl,A is single bond, Y⁰ is 4-amidino-2-fluorobenzyl, and M is CH; R² is3-aminophenyl, B is butyl, A is single bond, Y⁰ is 4-amidinobenzyl, andM is CH; R² is 3-aminophenyl, B is 3-methoxy-2-propyl, A is single bond,Y⁰ is 4-armiidinobenzyl, and M is CH; R² is 3-aminophenyl, B is3-methoxy-2-propyl, A is single bond, Y⁰ is 4-amidinobenzyl, and M isCH; R² is 3-aminophenyl, B is 2-methoxy-2-ethyl, A is single bond, Y⁰ is4-amidinobenzyl, and M is CH; R² is 3-aminophenyl, B is 2-propyl, A issingle bond, Y⁰ is 5-amidino-2-thienylmethyl, and M is CH; R² is3-aminophenyl, B is 2-propyl, A is single bond, Y⁰ is4-amidino-3-fluorobenzyl, and M is CH; R² is 3-carboxyphenyl, B is2-propyl, A is single bond, Y⁰ is 4-amidinobenzyl, and M is CH; R² is3-aminophenyl, B is 2-propyl, A is single bond, Y⁰ is4-amidino-3-fluorobenzyl, and M is CH; or R² is 3-aminophenyl, B is2-propyl, A is single bond, Y⁰ is 4-amidino-3-fluorobenzyl, and M is CH.11. A compound having the Formula:

or a pharmaceutically acceptable salt thereof, wherein; B is C3-C7cycloalkyl wherein (a) each ring carbon is optionally substituted withR³³, (b) a ring carbon other than the ring carbon at the point ofattachment of B to A is optionally substituted with oxo provided that nomore than one ring carbon is substituted by oxo at the same time, (c) aring carbon in a first alpha position relative to the ring carbon at thepoint of attachment is optionally substituted by R⁹, (d) a ring carbonin a second alpha position relative to the ring carbon at the point ofattachment is optionally substituted by R¹³, (e) a ring carbon, ifpresent, in a first beta position relative to the ring carbon at thepoint of attachment and in an alpha position relative to the ring atomoptionally substituted by R⁹, is optionally substituted by R¹⁰, (f) aring carbon, if present, in a second beta position relative to the ringcarbon at the point of attachment and in an alpha position relative tothe ring atom optionally substituted by R¹³, is optionally substitutedby R¹², (g) a ring carbon, if present, in a first gamma positionrelative to the ring carbon at the point of attachment and in an alphaposition relative to the ring atom optionally substituted by R¹⁰, isoptionally substituted by R¹¹, and (h) a ring carbon, if present, in asecond gamma position relative to the carbon at the point of attachmentand in an alpha position relative to the ring atom optionallysubstituted by R¹², is optionally substituted by R³³; R⁹, R¹¹, and R¹³are independently selected from the group consisting of hydrogen,hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkoxy,alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl,alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido,and cyano; R¹⁰ and R¹² are independently selected from the groupconsisting of hydrogen, acetamido, haloacetamido, amidino, guanidino,alkyl, alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino, loweralkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl,dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl,carboalkoxy, carboxy, carboxyalkyl, carboxyamido, and cyano; R³³ isselected from the group consisting of hydrogen, amidino, guanidino,alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio,amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl,halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy,carboxamido, cyano, and Q^(b); A is selected from the group consistingof single covalent bond and (CH(R¹⁵))_(pa)—(W⁷)_(rr) wherein rr is aninteger selected from 0 through 1, pa is an integer selected from 0through 3, and W⁷ is N(R⁷); R⁷ is selected from the group consisting ofhydrogen and alkyl; R¹⁵ is selected from the group consisting ofhydrogen, halo, alkyl, and haloalkyl; M is R¹—C; R¹ is selected from thegroup consisting of hydrogen, hydroxy, hydroxyamino, amidino, amino,cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio,alkoxyamino, haloalkyl, haloalkoxy, and halo; R² is Z⁰—Q; Z⁰ is acovalent single bond; Q is selected from the group consisting of aryland 5- or 6-membered heteroaryl wherein the heteroatoms of saidheteroaryl are selected from oxygen, nitrogen, and sulfur, and (a) aring carbon in a first alpha position relative to the ring carbon at thepoint of attachment is optionally substituted by R⁹, (b) a ring carbonin a second alpha position relative to the ring carbon at the point ofattachment is optionally substituted by R¹³, (c) a ring carbon, in afirst beta position relative to the ring carbon at the point ofattachment and in an alpha position relative to the ring atom optionallysubstituted by R⁹, is optionally substituted by R¹⁰, (d) a ring carbon,in a second beta position relative to the ring carbon at the point ofattachment and in an alpha position relative to the ring atom optionallysubstituted by R¹³, is optionally substituted by R¹², and (e) a ringcarbon, if present, in the gamma position relative to the ring carbon atthe point of attachment and in an alpha position relative to each of thering atoms optionally substituted by R¹⁰ and R¹², respectively, isoptionally substituted by R¹¹; R⁹, R¹¹, and R¹³ are independentlyselected from the group consisting of hydrogen, hydroxy, amino, amidino,guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulfinyl,alkylsulfonyl, amidosulfonyl, monoalkylamidosulfonyl, alkyl, halo,haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano;R¹⁰ and R¹² are independently selected from the group consisting ofhydrogen, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy,alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino,alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkylamidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl, carboalkoxy,carboxy, carboxyamido, carboxyalkyl, and cyano; Y⁰ is formula (IV):

 wherein D⁵, D⁶, J⁵, and J⁶ are independently selected from the groupconsisting of C, N, O, S and a covalent bond with the provisos that nomore than one is a covalent bond, no more than one of D⁵, D⁶, J⁵, and J⁶is O, no more than one of D⁵, D⁶, J⁵, and J⁶ is S, one of D⁵, D⁶, J⁵,and J⁶ must be a covalent bond when two of D⁵, D⁶, J⁵, and J⁶ are O andS, and no more than four of D⁵, D⁶, J⁵, and J⁶ are N; R¹⁶, R¹⁷, R¹⁸, andR¹⁹ are independently selected from the group consisting of hydrogen,amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino,lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl,haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl,aminoalkyl, and cyano; Q^(b) is selected from the group consisting ofhydrogen, NR²⁰R²¹, and C(NR²⁵)NR²³R²⁴; R²⁰, R²¹, R²³, R²⁴, and R²⁵ areindependently selected from the group consisting of hydrogen and alkyl;and Q^(s) is CH₂.
 12. A compound of claim 11, or a pharmaceuticallyacceptable salt thereof,

wherein: R² is 3-aminophenyl, B is cycylopropyl, A is single bond, Y⁰ is4-amidinobenzyl, and M is CH; R² is 3-aminophenyl, B is cyclobutyl, A issingle bond, Y⁰ is 4-amidino-2-fluorobenzyl, and M is CH; R² is3-aminophenyl, B is cyclobutyl, A is single bond, Y⁰ is 4-amidinobenzyl,and M is CH; R² is 3-aminophenyl, B is cyclopropyl, A is single bond, Y⁰is 4-amidino-2-fluorobenzyl, and M is CH; R² is 3-aminophenyl, B iscyclobutyl, A is single bond, Y⁰ is 4-amidinobenzyl, and M is CH; R² is3-aminophenyl, B is cyclobutyl, A is single bond, Y⁰ is4-amidino-3-fluorobenzyl, and M is CH; R² is 3-aminophenyl, B iscyclopentyl, A is single bond, Y⁰ is 4-amidinobenzyl, and M is CH; R² is5-amino-2-thienyl, B is cyclobutyl, A is single bond, Y⁰ is4-amidinobenzyl, and M is CH; R² is 3-aminophenyl, B is cyclopropyl, Ais CH₂, Y⁰ is 4-amidinobenzyl, and M is CH; R² is 3-aminophenyl, B is2-(2R)-bicyclo[2.2.1]-heptyl, A is single bond, Y⁰ is 4-amidinobenzyl,and M is CH; R² is 3-aminophenyl, B is cyclopentyl, A is single bond, Y⁰is 4-amidino-2-fluorobenzyl, and M is CH; R² is 3-aminophenyl, B iscyclohexyl, A is CH₂CH₂, Y⁰ is 4-amidinobenzyl, and M is CH; R² is2-hydroxyphenyl, B is cyclobutyl, A is single bond, Y⁰ is4-amidinobenzyl, and M is CH; R² is phenyl, B is cyclobutyl, A is singlebond, Y⁰ is 4-amidinobenzyl, and M is CH; R² is 3-thienyl, B iscyclobutyl, A is single bond, Y⁰ is 4-amidinobenzyl, and M is CH; R² is2,6-dichlorophenyl, B is cyclobutyl, A is single bond, Y⁰ is4-amidinobenzyl, and M is CH; R² is 3-aminophenyl, B is cycylopropyl, Ais single bond, Y⁰ is 4-amidinobenzyl, and M is CF; R² is 3-aminophenyl,B is cyclobutyl, A is single bond, Y⁰ is 4-amidino-2-fluorobenzyl, and Mis CF; R² is 3-aminophenyl, B is cyclobutyl, A is single bond, Y⁰ is4-amidinobenzyl, and M is CF; R² is 3-aminophenyl, B is cyclopropyl, Ais single bond, Y⁰ is 4-amidino-2-fluorobenzyl, and M is CF; R² is3-aminophenyl, B is cyclobutyl, A is single bond, Y⁰ is 4-amidinobenzyl,and M is CF; R² is 3-aminophenyl, B is cyclobutyl, A is single bond, Y⁰is 4-amidino-3-fluorobenzyl, and M is CF; R² is 3-aminophenyl, B iscyclopentyl, A is single bond, Y⁰ is 4-amidinobenzyl, and M is CF; R² is5-amino-2-thienyl, B is cyclobutyl, A is single bond, Y⁰ is4-amidinobenzyl, and M is CF; R² is 3-aminophenyl, B is cyclopropyl, Ais CH₂, Y⁰ is 4-amidinobenzyl, and M is CF; R² is 3-aminophenyl, B is2-(2R)-bicyclo[2.2.1]-heptyl, A is single bond, Y⁰ is 4-amidinobenzyl,and M is CF; R² is 3-aminophenyl, B is cyclopentyl, A is single bond, Y⁰is 4-amidino-2-fluorobenzyl, and M is CF; R² is 3-aminophenyl, B iscyclohexyl, A is CH₂CH₂, Y⁰ is 4-amidinobenzyl, and M is CF; R² is2-hydroxyphenyl, B is cyclobutyl, A is single bond, Y⁰ is4-amidinobenzyl, and M is CF; R² is phenyl, B is cyclobutyl, A is singlebond, Y⁰ is 4-amidinobenzyl, and M is CF; R² is 3-thienyl, B iscyclobutyl, A is single bond, Y⁰ is 4-amidinobenzyl, and M is CF; or R²is 2,6-dichlorophenyl, B is cyclobutyl, A is single bond, Y⁰ is4-amidinobenzyl, and M is CF.
 13. The compound as recited in claim 11 ora pharmaceutically acceptable salt thereof, wherein; B is selected fromthe group consisting of cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, 2-(2R)-bicyclo[2.2.1]-heptyl, andbicyclo[3.1.0]hexan-6-yl, wherein (a) each ring carbon is optionallysubstituted with R³³, (b) a ring carbon in a first alpha positionrelative to the ring carbon at the point of attachment is optionallysubstituted by R⁹, (c) a ring carbon in a second alpha position relativeto the ring carbon at the point of attachment is optionally substitutedby R¹³, (d) a ring carbon, if present, in a first beta position relativeto the ring carbon at the point of attachment and in an alpha positionrelative to the ring atom optionally substituted by R⁹, is optionallysubstituted by R¹⁰, and (e) a ring carbon, if present, in a second betaposition relative to the ring carbon at the point of attachment and inan alpha position relative to the ring atom optionally substituted byR¹³, is optionally substituted by R¹²; R⁹, R¹¹, and R¹³ areindependently selected from the group consisting of hydrogen, methyl,ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino,N,N-dimethylamino, methylthio, trifluoromethyl, pentafluoroethyl,2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl,N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl,1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, carboxy, andcyano; R¹⁰ and R¹² are independently selected from the group consistingof hydrogen, amidino, amidocarbonyl, N-methylamidocarbonyl, guanidino,methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, 1-hydroxyethyl,2-hydroxyethyl, carboxy, carboxymethyl, amino, acetamido,trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl,trifluoroacetamido, aminomethyl, N-methylamino, dimethylamino,amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl,methoxycarbonyl, fluoro, chloro, bromo, and cyano; R³³ is independentlyselected from the group consisting of hydrogen, amidino, guanidino,methyl, ethyl, methoxy, ethoxy, hydroxy, carboxy, amino, N-methylamino,dimethylamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl,2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl,N-methylamidosulfonyl, hydroxymethyl, amidocarbonyl, cyano, and Q^(b); Ais selected from the group consisting of single covalent bond, NH,N(CH₃), CH₂, CH₃CH, CH₂CH₂, and CH₂CH₂CH₂; M is R¹—C; R¹ is selectedfrom the group consisting of hydrogen, hydroxy, amino, amidino,hydroxyamino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl,methoxy, hydroxymethyl, methoxyamino, methylthio, trifluoromethoxy,fluoro, and chloro; R² is selected from the group consisting of phenyland 2-thienyl, 2-furyl, 2-pyrrolyl, 2-imidazolyl, 2-thiazolyl,3-isoxazolyl, 2-pyridyl, and 3-pyridyl heteroaryl rings, wherein (a) aring carbon in a first alpha position relative to the ring carbon at thepoint of attachment is optionally substituted by R⁹, (b) a ring carbonin a second alpha position relative to the ring carbon at the point ofattachment is optionally substituted by R¹³, (c) a ring carbon, in afirst beta position relative to the ring carbon at the point ofattachment and in an alpha position relative to the ring atom optionallysubstituted by R⁹, is optionally substituted by R¹⁰, (d) a ring carbon,in a second beta position relative to the ring carbon at the point ofattachment and in an alpha position relative to the ring atom optionallysubstituted by R¹³, is optionally substituted by R¹², and (e) a ringcarbon, if present, in the gamma position relative to the ring carbon atthe point of attachment and in an alpha position relative to each of thering atoms optionally substituted by R¹⁰ and R¹², respectively, isoptionally substituted by R¹¹; Y⁰ is selected from the group consistingof:

R¹⁶, R¹⁷, R¹⁸, and R¹⁹ are independently selected from the groupconsisting of hydrogen, methyl, ethyl, amidino, guanidino, methoxy,hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino,dimethylamino, methylthio, ethylthio, trifluoromethylthio,methylsulfinyl, methylsulfonyl, trifluoromethyl, pentafluoroethyl,2,2,2-trifluoroethyl, trifluoromethoxy, fluoro, chloro, amidosulfonyl,N-methylamidosulfonyl, hydroxymethyl, carboxy, and cyano; Q^(b) isselected from the group consisting of NR²⁰R²¹ and C(NR²⁵)NR²³R²⁴; R²⁰,R²¹, R²³, R²⁴, and R²⁵ are independently selected from the groupconsisting of hydrogen, methyl, and ethyl; and Q^(s) is CH₂.
 14. Thecompound as recited in claim 13 or a pharmaceutically acceptable saltthereof, wherein; B is selected from the group consisting ofcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and2-(2R)-bicyclo[2.2.1]-heptyl; A is selected from the group consisting ofa single covalent bond, CH₂, NHC(O), CH₂CH₂ and CH₂CH₂CH₂; M is R¹—C; R¹is selected from the group consisting of hydrogen, hydroxy, amino,methyl, trifluoromethyl, fluoro, and chloro; R² is selected from thegroup consisting of 3-aminophenyl, 2,6-dichlorophenyl, 2-hydroxyphenyl,5-amino-2-thienyl, and 3-thienyl; Y⁰ is selected from the groupconsisting of:

R¹⁶ and R¹⁹ are independently selected from the group consisting ofhydrogen, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy,hydroxymethyl, fluoro, chloro, and cyano, R¹⁷ and R¹⁸ are independentlyselected from the group consisting of hydrogen, fluoro, chloro, hydroxy,hydroxymethyl, amino, carboxy, and cyano; Q^(b) is selected from thegroup consisting of hydrogen and C(NR²⁵)NR²³R²⁴; R²³, R²⁴, and R²⁵ areindependently selected from the group consisting of hydrogen and methyl;and Q^(s) is CH₂.
 15. The compound as recited in claim 14 or apharmaceutically acceptable salt thereof, wherein; B is selected fromthe group consisting of cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and 2-(2R)-bicyclo[2.2.1]-heptyl; A is selected from thegroup consisting of a single covalent bond, CH₂, CH₂CH₂ and CH₂CH₂CH₂; Mis R¹—C; R¹ is selected from the group consisting of hydrogen, fluoro,and chloro; R² is selected from the group consisting of 3-aminophenyl,2,6-dichlorophenyl, 2-hydroxyhenyl, phenyl, 5-amino-2-thienyl, and3-thienyl; and Y⁰ is selected from the group consisting of5-amidino-2-thienylmethyl, 4-amidinobenzyl, 2-fluoro-4-amidinobenzyl,and 3-fluoro-4-amdinobenzyl.